Immunology Cornell Notes

Chapter 1: Introduction to the Immune System
The entire human immune system can be categorized into: Innate

Immunity and Adaptive Immunity which are connected via cytokines
signaling as well as dendritic cells.
Innate Immunity
What is innate immunity and The Innate Immune System is the body’s first line of defense against
how is it initiated? pathogens (disease-causing microorganisms). It is fast and nonspecific,
What are some meaning it responds the same way to all types of pathogens which makes
characteristics of innate it very effective. It also lacks memory/recollection of past immune
immunity? responses.
Innate Immunity consists of:
● Natural barriers such as the skin, mucous linings, saliva, tears
which prevent microbe entry.
● Phagocytic, nonspecific cells called leukocytes such as

What are the cells and monocytes/macrophages, neutrophils, dendritic cells, eosinophils,
molecules involved in innate mast cells, basophils, which detect the foreign microbe using
immunity? pattern recognition receptors and destroy them using
phagocytosis.
● Complement Cascades and Mediators such as interferons,

mannan-binding lectin (MBL), proteases, which initiate and amplify
innate immune responses.
Innate Immune responses are triggered within minutes upon identification

How is innate immunitry
triggered? of microbe entry into the body.
Innate and Adaptive immunity are connected by cytokines and dendritic cells. Innate immunity is the first
defense and uses nonspecific phagocytic cells, natural barriers and complements. It is triggered by
microbe entry or microbial invasion of a natural barrier.
Adaptive Immunity
The Adaptive Immune System is the second line of defense which is
What is adaptive immunity triggered by cytokines when the innate immune system fails to stop an
and how is it initiated?
invasion. It is slow but very specific (has a particular adaptive immune
What are some characteristics
of adaptive immunity? response for each particular microbe). It also has memory, meaning it
retains immunological info about previous encounters with the microbes
in order to improve its immune response.
Adaptive Immunity consists of:

● Lymphocytes, which are T and B lymphocytes, that use antigen
recognition molecules to bind with nonself antigens.
● Antigen Recognition Molecules which are the diverse repertoire

What are the cells and
molecules involved in of antigen receptors located on the B & T lymphocytes that
adaptive immunity? identify and bind to specific epitopes on a nonself antigen.
● Antigen Presenting Cells which are Molecules such as dendritic

cells or major histocompatibility complex (MHC)/human leukocyte
antigen (HLA) that bind to antigens and present them to T
lymphocytes.
How are adaptive immune
responses initiated? Adaptive Immune responses are triggered upon recognition of a nonself
antigen within the body by a lymphocyte with the receptor for the epitope
of that antigen. This response is slow and usually takes days.
Innate and Adaptive Immunity are interconnected:

● Cells from innate immunity such as dendritic cells, interferons
How are the Innate and and macrophages affect the cells of adaptive immunity.
Adaptive Immune Systems ● Both systems rely on cytokines for cell-cell communication during
connected? immune responses and immune cell migration to
infected/inflamed sites.
How do they differ in immune
response and antigen ● Adaptive immunity is triggered if innate immunity fails to
recognition? neutralize an invasion.
The immune system only needs to identify one antigen of a
pathogen/microbes, they don’t need to identify every single possible
antigen.
Adaptive Immunity is the second defense response and is triggered upon innate immunity failure. It uses
lymphocytes with specificity, antigen recognition based on epitopes and antigen presenting cells. Innate
and adaptive immunity are connected because they rely on cytokines, dendritic cells and the success of
the first response (innate) to be respond to an invasion. They differ in immune response (specific vs
nonspecific, fast vs slow, first response vs second response, antigen recognition vs pattern recognition).
Differentiate between Self-antigens are receptors on cells native to the body whereas non-self antigens
self and nonself are receptors on foreign cells that trigger an immune response when they enter
antigens? How do the body.
receptors recognize ● Receptors bind to their cognate antigens whose epitope they are specific
antigens? for. A single antibody can have receptors for one epitope (monoclonal) or
multiple epitopes (polyclonal).
Lymphocytes account for the variety of epitopes exist for each antigen through
their diverse repertoire of receptors:
● Immunoglobulins (Ig) or antibodies (Ab) in B cells T Cell receptors (TCR)
inT Cells).
What is clonal Clonal distribution creates this diversity. It is the process by which the unique
distribution?How does it receptor of every lymphocyte is distributed/shared among their daughter cells
impact receptor after proliferation upon meeting the appropriate antigen.
diversity? ● This results in multiple effector cell clones with the appropriate receptors
(T Cells) or multiple daughter cells that secrete the specific Ig needed (B
Cells).
Other characteristics of lymphocytes:

● Memory: They remember previously encountered antigens which leads to
How does greater immunity against microbes. This is why vaccination protects
understanding immunity against diseases.
affect medical advances ● Immunodeficiency: An insufficient amount of immune cell activity due to
like organ transplanting missing immune components (like the cells, receptors, molecules,
and vaccination? organs/tissues)
● Autoimmunity: Detection of normal self-antigens which initiates an
How does immune response against normal non-pathogenic body cells. This leads
understanding immunity to autoimmunity when unregulated.
affect knowledge of ● Allergies and Organ Rejection: They can produce an immune response
illnesses like against non-self antigens that are generally harmless but antigenically
autoimmunity or similar to a pathogenic antigen, leading to allergies (immune
allergies? hypersensitivity). They can also attack nonself antigens from transplanted
organs; this is when the body "rejects" the organ. In a situation like this,
the immune system must be suppressed to prevent immune responses.
Immune cells differentiate self from nonself antigens using receptors (Ig and TCR) and clonal distribution
to detect epitopes on antigens and eliminate them. Clonal distribution for self-antigens or harmless
non-self antigens causes autoimmunity, hypersensitivity or organ rejection during a transplant. Proper
immune response provides immunity against microbes, vaccines and successful organ transplants.
Lacking immune components causes immunodeficiency.
Chapter 2: Basic Concepts and Components of the Immune System
What are innate immune Innate cells use pattern recognition. Pattern recognition works by
cells? How do they recognize identifying molecular structures and patterns on the surface of
antigens? pathogens. Molecules/receptors that use this are:
● Toll-Like Receptors (TLRs) which recognize structures on
microbes/pathogens
● Mannan-binding lectin which recognizes the sugar mannose on
microbial surfaces
It also has cells that induce apoptosis such as Natural Killer cels (NK
cells) and uses interferon molecules of virally infected cells to prevent
replication of the virus.
Describe the process of Antigen recognition works by identifying epitopes and antigenic
antigen recognition compared determinants on antigens then binding with them to form a
to pattern recognition. ligand-receptor bond (lock and key).
● “Best fit” is the term used to describe a receptor’s affinity binding
with an appropriate epitope.
Why is Best Fit important in ● This is necessary to create an anticipatory defense against all
an immune response?
kinds of antigens so adaptive immune cells must express a great
Why is adaptive immunity an diversity of receptors in order to do this.
anticipatory defense system? ● Immunological memory amplifies this as it allows lymphocytes
(Remember recognition, that previously encountered an antigen to have receptors readily
memory and diversity). available for any more exposure to that antigen (or similar
antigens; cross reactivity).
Diversity and memory are created by:

● Clonal expansion where the lymphocyte proliferates upon
activation by an antigen to produce clones with appropriate
What processes allow for receptors for that antigen.
adaptive cell memory? ● Somatic gene rearrangement where gene fragments are
rearranged and combined to create a diverse repertoire of
receptors that are possible to have a best fit with all antigens.
Both cells started as ancestral genes but innate genes remained

relatively the same whereas adaptive genes undergo duplication and
specialization to create TCRs MHC molecules and Antibodies (Abs).
Innate cells use pattern recognition which recognizes molecular structures and patterns on cell surfaces
whereas adaptive cells use antigen recognition which recognizes pathogenic antigens and their
determinants. Adaptive immunity is anticipatory due to its antigen recognition/best fit, memory of
recognition and diversity in recognition molecules. It uses clonal expansion and somatic rearrangement to
maintain the best fit of its cells. All immune cells started as ancestral genes but innate cells barely had
change whereas adaptive cells undergo much differentiation and specialization.
Adaptive immunity is specific, diverse and has immunological memory

meaning it responds based on the antigen, it has a variety of receptors
for each antigen and it remembers previous encounters with antigens.
It can further be divided into subtypes of adaptive immunity:
What is humoral and ● Humoral Immunity by which mature B cells called plasma cells
cell-mediated immunity? secrete Igs to produce serum antibodies against antigens. B cells
Describe their differences bind directly to the antigen’s epitopes.
● Cell-Mediated Immunity by which cytotoxic T cells, NK cells and
What are the fundamental macrophages terminate an infected cell or pathogen. It requires
properties of adaptive antigen processing and presenting since T Cells bind only to
immunity?
antigens displayed by an MHC molecule on an APC. APCs
include dendritic cells, macrophages, MHC molecules and B
Cells.
Another pair of immunity subdivisions exists:
Describe passive and active ● Active Immunity is a form of immunity acquired through
immunity. exposure to a particular pathogen that triggers an immune
response.
● Passive Immunity is a form of immunity acquired through
transferring the immune cells/serum of the immunized person to
the unimmunized person.
Active Immune responses occur in phases:

Describe the process of an ● Cognitive Phase: Antigen encounters a cell with receptors
immune response.
appropriate for its epitope which activates the cell.
● Activation Phase: The activated cell proliferates to produce
clones with the appropriate receptors. The immune cells then
undergo differentiation which produces changes that enable an
immune response.
● Effector Phase: The antibodies and lymphocytes involved in the
response neutralize the antigens. B cells secrete Igs and T Cells
trigger cell apoptosis/lysis.
Additional steps are taken to downregulate the response once the threat
is neutralized.
Adaptive immunity can be described as humoral (from secretory antibodies of B cells) or cell-mediated
(from cytotoxic T Cells that induce apoptosis). Immunity can also be described as active (formed from
exposure to antigen) or passive (passed on from one immunized individual to an unimmunized
individual). Active immune response occur in phases: Cognitive: encounter with antigen then Activation:
to cause proliferation/differentiation then the Effector: cells neutralize the pathogen. Once the pathogen is
neutralized, the immune response is downregulated.
Types of Immune Responses:

What determines an immune Immune responses are dependent on the type/zoology of the microbe
response? invading the body and their site within the body:
● Intracellular pathogens; (viruses, some bacteria and parasites),

live within cells. They trigger innate responses (interferon,
macrophages, NK cells) and adaptive responses (IgM, IgA, IgG,
TH1 T cells, cytotoxic T lymphocytes). Inappropriate immune
responses may cause autoimmune diseases.
● Surface pathogens; (worms, arthropods and protozoa), infect
barriers such as the skin and mucus linings and surfaces. They
What are three types of trigger innate responses (mast cells, eosinophils) and adaptive
triggers for immune responses (TH2 T Cells, IgE). Inappropriate immune responses
responses? may cause allergies
● Extracellular pathogens; (bacteria and fungi), exist in the
extracellular matrix between cells. They trigger innate responses
(neutrophils) and adaptive responses (TH17 T Cells).
Inappropriate immune responses may cause autoimmune
disease.
Overview of all Immune Cells:
Immune responses are based on the type and location of the microbe. It can be an extracellular pathogen
living in matrices between cells, intracellular living among cellular components or surface infecting
barriers. Failed extracellular and intracellular responses may cause autoimmunity and failed surface
responses may cause allergies. Each pathogen triggers different innate and adaptive immune cells.
Chapter 3: Introduction to Antigen Recognition
What are the antigen The antigen recognition molecules are B Cell receptors (BCRs), T Cell
recognition molecules? receptors (TCRs) and MHC molecules.
● BCRs are immunoglobulins, and when secreted by a plasma
cell, they are soluble antibodies free-flowing in the blood which
binds antigens directly.
● TCRs are receptors found on the surface of T Cells that form a
receptor-ligand-MHC molecule complex to recognize antigens.
● MHC molecules are derived from a cluster of genes known as
human leukocyte antigens (HLA). They peasant antigen peptides
to T Cells.
They all share a similar structure of a polypeptide chain, Ig domain/fold
How can a molecule be a part
of the superfamily? and an extended surface which makes them a part of the
immunoglobulin superfamily.
MHC has two classes: MHC Class 1 found on all cells and MHC
Class 2 found on APCs. They present antigen peptides to T Cells and
regulate NK cells.
What are the MHC
● Every individual has 6 different MHC Class 1 and 8 different
subdivisions/classes?
Compare MHC diversity to MHC Class 2 molecules which are all the same in one individual
BCR and TCR diversity? but vary greatly across a population.
● BCRs and TCRs differ in every lymphocyte in an individual’s
body.
● MHC is polygenic meaning it is encoded by multiple genes
(Class 1; HLA-A, -B, -C genes and Class 2: HLA-DP, -DQ, -DR
genes). It is polymorphic meaning its genes have various alleles.
The antigen recognition molecules are BCRs (immunoglobulins/soluble antibodies of BCells), TCRs (from
T Cells) and MHC molecules (from HLA genes). They are a part of the immunoglobulin superfamily
because they share a domain similar to immunoglobulin. MHC has two main classes, Class 1- HLA-A,
B,C and Class 2 HLA-DP, DQ, DR, which are polygenic and polymorphic in nature/structure.
Chapter 4: Antigens and Antibody Structure
Antigens are categorized according to tier immune responses:

● Immunogen: large, complex antigens of 20 different amino acids
that elicit an immune response. Example hepatitis B virus.
● Haptens: Antigens that are able to bind to receptors but are too
small to trigger an immune response. They must be bound to a
How are antigens macromolecule carrier to form a hapten-carrier conjugate which
categorized? will trigger a response. Example Penicillin.
Define each type and give an ● Tolerogen: Antigens that the adaptive immune system has been
example. programmed not to respond to.
As well as their origins:

● Haptens and Immunogens are derived from pathogens.
● Proteins from other individuals such as cells or MHC from organ
transplants are alloantigens that elicit a strong immune response.
● Tolerogens are antigens derived from foods but become
allergens when tolerization goes wrong, and also may cause
normal host cells to become autoantigens.
Epitopes are molecular structures found on large antigens that bind to

What are epitopes and how TCRs and antibodies/Igs. They are categorized according to shape
important are they in immune which also affects which receptors they binds to:
responses? (Relate to their ● Discontinuous or conformational epitopes:
structure) Discontinuous/noncontiguous areas of the polypeptide chain
brought together which makes a 3-dimensional shape.
● Continuous/Liner epitopes: Contiguous areas of the polypeptide
chain of 12 to 22 amino acid residues.
● T Cells recognize linear epitopes because of how antigens are
presented to them whereas B Cells recognize both types.
Antigens are categorized according to their immune responses and origins; immunogens and haptens
trigger immune responses and are from pathogens, tolerogens are from foods and normally do not trigger
immune responses, alloantigens are found in organ transplantation and trigger an immune response.
Epitopes are molecular structures on antigens used in binding during an immune response.
Discontinuous epitopes 3-d shaped epitopes that bind to B cells only Continous epitopes are linear
epitopes that bind to both T and BCells.
What are the Antibodies are soluble proteins that bind to the antigen that triggered it’s
characteristics of production. It relies on:
antibodies? ● Specificity: Antibodies are highly specific to the antigenic
determinants of a particular antigen thus they bind only to that
appropriate antigen.
● Affinity: When antibodies do bind, they do so strongly/with a high
affinity.
● They make up 20% of plasma proteins and can be separated into
gamma globulin fractions of serum (γ-zone) and antibody-bearing
fraction of serum (polyclonal immunoglobulins). Gamma has the most
activity.
What is monoclonality ● The antibodies that respond to a single particular antigen with multiple
and polyclonality in epitopes are heterogeneous because they are derived from different
antibodies? clones of B cells with Igs for different epitopes on the antigen.
● Homogenous Igs in serum are secreted from single clones of B cells
after proliferation. They are specific for one epitope on the antigen.
Describe antibody
structure. Antibody structure consists of:
Two Light and Two Heavy Chains linked together by disulfide bonds:
● Heavy chains can be either μ (mu) for IgM, δ (delta) for IgD, γ
(gamma) for IgG, ε (epsilon) for IgE, and α (alpha) for IgA. and define
the biological properties of the antibody.
● Light chains are either types, κ (kappa) or λ (lambda) and one is
present per antibody.
Antibodies depend on the specificity of their binding to the appropriate epitope and the affinity of that
binding being strong enough to form a complex. Antibodies specific for one epitope are monoclonal
whereas specificity for multiple epitopes are polyclonal. Antibodies consist of 2 heavy chains (dependent
on Ig class) and 2 light chains (only one present per Ig).
Both chains consist of a variable region (VL and VH) and a constant
region (CL and CH):
● C regions carry out biologic effector functions like binding with
complements and V regions bind antigens.
Describe the chain, segments
and folded domain of an ● The variable regions of both chains are 110 amino acids at the
antibody. N-terminus. The constant regions in light chains are 215 and in
heavy chains, 450.
Both chains are domain/Immunoglobulin folds which are folded repeated

segments of 110 residues:
● Light chains consist of one variable domain and one constant
domain. Heavy chains consist of one variable domain and 3 or
more constant domains.
Two fragmented regions that are produced by proteolytic digestion of Igs

by enzymes pepsin and papain:
● Fragment antigen binding (Fab) which binds antigens and
Fraction crystallizable (Fc) which activates complement cascade.
● Pepsin degrades Ig into F(ab′)2 fragment and a degraded Fc
fragment. Papain that cleaves Ig at the hinge to produce two Fab
What does papain and pepsin fragments and an Fc fragment.
digestion of an
immunoglobulin produce?
Each chain in an antibody consists of a variable (binding) and constant (biologic effector) region that
forms a domain, except for heavy chain which has 3 or more constant domains. Proteolytic digestion of
Igs using pepsin produces F(ab′)2 and a degraded Fc reion whereas using papain produces Fab and Fc.
What are the types of Antibodies have varying methods to neutralize a pathogen. They may
antibodies and how do they agglutinate/clump a pathogen and coat it with antibodies to facilitate
function? phagocytosis, to initiate cell lytic reactions or to activate complements.
How do they differ (describe
The difference in functions is as a result for structural differences that
it).
create Ig classes.
● *IgM has 10 binding sites which is why it is the main Ab and used
in early responses. It also has a pentameric structure composed
of five H2L2 linked by a joining chain (J chain).
● IgE’s allergy activity comes from its ability to trigger histamine
release and activate mast cells when it binds to an antigen while
coupled to Fc.
● Secreted IgA (sIgA) is coupled to 2 IgA molecules, a J chain and
a secretory complement which facilitates its transport across
epithelial cells into secretions and protects it from proteolytic
attack.
Antibodies are classified according to their roles in immune responses and the type of response required.
There is IgA which is a secreted Ig to barriers and used to tag pathogens for destruction, IgD that
stimulated IgM, IgE used which triggers histamine during allergy and parasiti responses, IgG which
crosses the placenta and binds to phagocytes and blood-borne pathogens and IgM which is the main
antibody having multiple sites and great memory.
Chapter 5: Antibody-Antigen Interactions
Similarly to enzyme-catalyst interactions, antibody-antigen reactions are

a form of receptor-ligand interaction that depends on goodness of fit.
Goodness of Fit in this case refers to:

Affinity: A Good Fit occurs When an antibody has high affinity for an
Describe Goodness of Fit and antigen, thus the sum of the weak noncovalent interactions are strong.
how it relates to a (Van der Waals Interactions, Hydrogen Bonding, Hydrophobic
receptor-ligand complex. Interactions, Electrostatic reactions between charged side chain)
(affinity and specificity)
Specificity: Antibody binding sites and antigens (and
epitopes/determinants) have chemical complementarity between the
chemical groups in the walls of the combining site. (The hypervariable
Describe cross reactivity in region (heavy and light chains -VH and LH)
regards to binding site variety
Cross Reactivity: Antibodies can exhibit multispecificity when they have
an affinity for and bind to another antigen that is structurally similar to
their specified antigen. This causes clinical illnesses like autoimmune
diseases and food/medicine allergies
How do binding sites vary?. Antibody Variety: Binding sites on antibodies vary in size and shape
according to the specific antigen or epitope they bind to.
Antibody-antigen complexes are a type of receptor-ligand relationship that relies on the goodness of fit,
meaning the binding site shape, binding affinity, specificity and cross reactive properties of the antibody
and antigen involved.
Why is understanding Antibody-Antigen Interactions form the foundation for a lot of diagnostic
cross-reactivity important and tests. Since cross reactivity causes illnesses, the amount and type of
how do immunoassays work? antigens or antibodies present in a sample should be defined. This is
done through Immunoassays:
ELISA:
Enzyme-Linked Immunosorbent Assay determines the amount of
antibody-antigen, proteins and glycoproteins present. Based on high
affinity and specificity between Ab-Ag interactions.
Describe ELISA test. (HIV, Lyme, Covid-19):
Give an example of a disease
detected using this.
● Antigen binds to well and the excess is washed off
● Patient serum is added and incubate and relevant primary

antibodies will bind to antigens present
● The well is washed again to remove irrelevant antibodies but the

antibody-antigen complexes remain due to their high affinity
● A secondary antibody from an animal conjugated to an enzyme

is added and binds to antibodies present to produce an amount
of coloured product that is proportional to the amount of
antibody-antigen complex present.
There are different types of ELISA. The method here was Indirect ELISA
where primary and conjugated secondary Abs are used. Direct ELISA
uses only a primary antibody conjugated to an enzyme. Sandwich ELISA
adds capture antibody first then antigen then primary Ab and conjugated
secondary Ab. Competitive ELISA uses competing sample/inhibitor Ag
and conjugated Ag of interest to compete for AB binding.
Cross reactivity of antigens and antibodies interactions can cause unintentional triggers resulting in
illness and autoimmune diseases. ELISA uses the affinity and specificity of Ab-Ag interaction to
determine the amount of Ab-Ag complexes present in a biological sample.
Describe the Lateral flow test. Lateral Flow Test:

Give an example of a disease It determines whether a protein, antigen or antibody is present in body
detected using this. fluid, example a pregnancy test. It is based on the capillary action
moving the sample/extract along immobilized antibodies
● Urine containing hCG encounters mouse antibody conjugated to

a coloured material against an epitope of hCG and becomes part
of an hCG antibody-bead complex
● The urine-antibody mixture encounters a second antibody

against a different hCG epitope which binds and captures the
antibody-bead complex to form a coloured line (but only if
sufficient hCG is present)
● The urine encounters a third antibody specific for mouse

immunoglobulin and produced in sheep which captures the last
few heads and produces another line (a control line indicating the
test worked)
This method was specific to pregnancy tests but this immunoassay was
also used during Covid-19 testing.
The Lateral flow test determines whether a biological sample is positive or negative for a particular
antibody or antigen using capillary action of the sample along a testing strip and capture complexes
placed throughout the strip.
Describe the Immunofluorescence:

immunofluorescence Assay. It uses antibodies covalently attracted to fluorochromes such as
Give an example of a disease fluorescein isothiocyanate (FITC) which couples to free amino groups on
detected using this. proteins. It is based on fluorescent dyes to detect ab-ag binding
(Lupus, Sclerosis, Syphilis).
● The test is used to detect antigens in cells or tissue sections and

to screen for autoantibodies to cell/tissue antigens.
● FITC emits a greenish light when exposed to UV light.

Fluorescence microscopes equipped with UV sources used to
examine specimens exposed to fluorescent antibodies.
● Direct test: Antibodies (sheep) are added on the biopsy section

and are directly linked to fluorescent compounds. The fluorescein
label emits visible light over the antigen of interest.
● Indirect test: Ligand that can identify the antibody is linked to the
fluorescent compound. Patient serum containing autoantibodies
bind to antigens on tissue specimen. Anti-human IgG (sheep)
binds to IgG and the bound IgG is detected under UV light.
Immunofluorescence uses antibodies and fluorophores/fluorescent dyes to detect the presence of Ag-AB
complexes within a sample. It can detect Lupus, Sclerosis, and Syphilis
Describe Flow Flow Cytometry

Cytometry. This technique is used to enumerate cells that express an antigen. It is based on
Give an example of a light scattering and fluorescence emission as cells bass through light beam
disease detected (Leukemia, Lymphoma, Malaria):
using this.
● Cells are stormed with antibody that is specific for the cell-surface antigen
● Lymphocytes are incubated with antibodies couple to fluorescent regents

and is then pass through the flow cytometer single file
● The number of stained cells can be counted (eg: number of CD4+ T Cells
present)
Flow cytometry is used to number cells that express a particular antigen using light and fluorescence. It can
detect leukemia and malaria.
Chapter 6: Antibody Diversity
What is the general Antibodies consist of a heavy and light chain; on each there is a variable (V) and
structure of an constant (C) region which are encoded by gene segments during B Cell
antibody? development.
*shaded is light chain

What are the gene The Gene Segments are:
segments? ● Leader Segment (L)
● Joining Segments (J)
● Diversity Segments (D)
● Variable and Constant Segments
The segments exist in sets which are arrays of different versions of the gene
segment. Eg: Jk set = 5 different Jk gene segments.
The gene segments undergo somatic recombination where the segments are
What processes do
the gene segments rearranged and combined to form a continuous function gene. This produces a
they undergo to repertoire of potential antibody molecules and is done during B Cell development
create receptor in the absence of antibodies.
diversity? ● The genes come from either chromosome 2 (k light chain) or chromosome
22 (h light chain) plus chromosome 12 (heavy chain)to produce
immunoglobulin. Each cell has two of these genes, one from each parent
but one must be silenced (via allelic exclusion).
After recombination, once the light and heavy genes are assembled, they are
synthesized and the polypeptide chains are assembled as an Ig molecule. The
synthesized Ig Molecule is then expressed at the surface of the B Cell or secreted
from a mature differentiated B Cell known as a plasma cell.
Antibodies consist of a heavy and light chain encoded by leader, joining and diversity segments which
exist in arrays. They undergo somatic recombination and allelic exclusion to be rearranged into a
continuous function gene to produce receptor diversity.
What is the purpose Recombination creates diversity by combining different genes to create different
of the recombination V regions. This reduces the number of genes needed to account for all the
and rearranging of different antibodies and the amount of genome allocated for these genes. Eg: V1
gene segments? + K2 forms a different light chain than V6 + J2
So instead of having a thousand different genes for a thousand different Ab, the
gene segments are rearranged in different sequences.
The assembling of the light and heavy involves the entire gene being transcribed
including the exons (coding sequences) and the introns (noncoding sequences)
into a primary RNA transcript:
Describe the ● The complex of enzymes V(D)J recombinase is responsible for the
processes involved cleavage and rejoining of DNA during rearrangement in somatic
in rearrangement recombination of Ig genes. RAG1 & RAG2 are responsible for the first
and recombination. cleavage
● RNA splicing takes place whereby RNA processing enzymes remove the
intron sequences to produce a messenger RNA (mRNA) that can be
transcribed into the L peptide sequence and is then removed by proteolytic
enzymes.
● For the V region to be transcribed, the V region gene segments have to be

cut out and then grouped together by enzymes responsible for DNA
recombination.
How do the V
regions of light and ● V region of light chains consists of: One V segment + One J segment from
heavy chains differ? the arrays to create a light V exon.
● V region of heavy chains consists of: One V segment + One D segment

then One J segment is added from the arrays to create a heavy V exon.
The recombination and rearrangement are necessary to create diversity by reducing the amount of genes
required to create different receptors. Intron and exon transcription involves VDJ recombinase and RAG
enzymes cleaving and rejoining DNA, RNA splicing into mRNA and V gene segment recombination. V
light chains have one V segment and one J segment whereas heavy has one V and D then one J is
added.
Describe the process Light Chain Synthesis:

of Light chain
synthesis.
1. Somatic recombination occurs where DNA is rearranged as V-J joins it.

2. DNA transcribed to RNA (notice how the strand is now a single strand).
3. RNA splices into mRNA; removal of introns and joining L to V and J to C
4. Translation of mRNA into protein and proteolytic cleavage of L peptide
Heavy Chain Synthesis:

Describe the process
of heavy chain
synthesis.
1. First Somatic recombination; D-J joined and rearranged DNA is formed.

2. Second recombination occurs where V and DJ rearrange and join.
3. DNA is transcribed to primary RNA transcript.
4. RNA is spliced into mRNA which removes introns joining L to V, J to C and
introns in C region.
5. mRNA is translated to protein and proteolytic cleavage of L peptide and
glycosylation occurs.
So the heavy chain protein is formed and is assembled with the light chain to form
an Ig molecule
Ig molecule: light chain + heavy chain. The light chain undergoes one round of somatic recombination to
create a VJ segment then DNA is transcribed into RNA then spliced into mRNA an translated into protein.
Heavy chain undergoes two rounds of somatic recombination to form DJ segment then VDJ segment
which is then transcribed into RNA then spliced into mRNA and translated into protein.
Describe light chain

organization and
synthesis.
Describe heavy
chain organization
and synthesis.
Light chain is organized into 35 different V kappa genes and J kappa genes on chromosome 2 along a
long intron which ends in a C kappa exon. Heavy chain is organized into 50 V, 25 D and J segments on
chromosome 16.
Antibody diversity is created by genetic mechanisms, multiple combinations,

somatic hypermutation, affinity maturation and Ig class switching.
Genetic Mechanisms:
What are the genetic
mechanisms ● Germline Diversity and Combinatorial Diversity: V, D and J segments
involved in antibody are presented in multiple copies then VJ and VDJ segments can
diversity? recombine in multiple combinations. Example of Germline; 35 Vk
segments are available.
Example of Combinatorial: 35 Vk and 5 Jk segments = 175 (35*5) different
human k light chains with different variable regions.
● Junctional Diversity: Junctions are formed between gene segments

during DNA cleavage and the addition/subtraction of nucleotides (by
enzyme terminal deoxynucleotidyl transferase) to create a viable joint. This
allows different coding sequences at each joint to create diversity.
For example, during the joining of a VH to a DHJH segment, a nucleotide
can be deleted to change -Ala-Arg-Asn to Ala-Arg-Ile
Describe multiple Multiple Combinations:

combinations. ● Heavy chains can associate with any light chain and since both chains are
responsible for antigen-binding, they generate different antibody specificity
when randomly assorted.
For example, 200 different light chains associating in random combinations
with 2000 different heavy chains potentially create 420 (4*10^5) different
antibodies.
Describe somatic Somatic Hypermutation:

hypermutation. ● This occurs after antigen stimulation when the functional antibody gene
has been assembled and the B Cell is responding to an antigen. It
generates additional diversity in the V region of heavy and light chains by
introducing point mutations at a very high rate.
For example, a possible mutation can produce antibodies that have a
higher affinity for a specific antigen than the original antibody.
B Cells that express somatic hypermutation are preferentially selected for
maturation into plasmid cells which is called the affinity maturation of antibody
population.
Antibody diversity is created through germline diversity, combinatorial diversity and junctional diversity
which rearranges and recombines the gene segments V, D and J. It uses multiple combinations since
heavy chains can associate with any light chains and form random combinations. It also uses somatic
hypermutation after antigen exposure to create antibodies with higher affinity for an invading antigen.
What are some Affinity Maturation:

diversity mechanisms ● During persistent infection, the amount of antibody increases due to more
unique to B Cells? B cells being produced throughout the course of infection. Somatic
hypermutation is also taking place here so the antibodies are improved
Describe affinity
maturation. with higher affinity and some B cells that survive the infection become
memory cells of the B cells that secreted the improved immunoglobulin.
These memory cells now have higher affinity than the previous B Cells,
and once they proliferate, they produce B Cells with a high affinity.
Ig Class Switching: Class switching is the process by which Ig of B cells

undergo DNA recombination in their switch regions to become a different class of
What are the benefits Ig.
of Ig Class ● Diversity: Class switching allows B cells to tailor antibodies to specific
Switching? circumstances since using different constant regions means more
diversity because different effector functions are associated with different
C regions.
● Principle: There are CH genes for each class of Igs (IgM, IgD, IgG, IgE,
IgA) and the same VH exon can be used with different CH exon at
different times during an immune response. So a B cell might use IgM for
a blood infection but then undergo class switching to produce IgG when
the infection reaches tissues. The V region remains the same in both IgM
and IgG.
● Application: The levels of each Ig class present in the body can indicate
the type of infection occurring and its pattern of spread.
B Cells are capable of producing membrane-bound Ig and secreted Ig

(antibodies).
● Diversity: They are encoded in different CH exons; alternative RNA
How are B cells processing is used to generate either one.
differentiated as
bound Igs and ● Application: The membrane-bound form has 30 additional amino acids at
secreted Abs?
the C terminus of the heavy chain including 25 hydrophobic amino acids
which is another Ig in the B cell membrane so it can act like a receptor.
Antibody populations have affinity maturation over time due to somatic hypermutation after antigen
exposure. They are also able to undergo class switching where the constant region of the heavy chain is
switched to configure a different antibody structure and function according to the immune response
required. The B cells are able to differentiate into membrane-bound or secreted Ig based on different
constant region heavy chain exons.
Identify the
differences between
membrane-bound
and secreted Ig.
Membrane and secreted Ig differ in their mRNA and C terminal where membrane-bound Ig has a chort tail
jutting into the cytoplasm.
Chapter 7: The T Cell Receptor
What are TCRs? T Cell Receptors (TCR) are heterodimeric (having 2 polypeptide chains that differ
in composition) membrane proteins that exist as αβ chains or γδ chains.
αβ TCR
● They are found in 95% of MHC-restricted T lymphocytes.
What are the
different kinds of ● They recognize peptide antigens presented by MHC molecules. This is the
TCR? How do they
TCR that is referred to when discussing most T Cells and cytotoxic T cells
differ in function and
structure? that kill virally infected cells.
γδ TCR
● They are found in 5% of T cells and are more numerous in some epithelial
tissues. They are a first line of defense and may initiate a response against
microbes at epithelial boundaries such as the skin.
● They are derived from the thymus from a separate cell lineage from the
cells that express the other receptor chain type.
● They recognize lipid molecules and peptide molecules but do not always
recognize MHC and are not restricted by them.
Uniqueness from Ig
What are some ● Each chain has a molecular weight of 40k to 60k. The extracellular portion
differences between of each chain has two domains.
TCR and Ig.
● Antigen binds to a site created by the V domains of both chains. The TCR
has fewer C region genes than Ig (one Cα gene, two functionally identical
Cβ genes. Ig C regions include the μ, δ, γ, ε, and α classes and the
λ-subtypes)
● The V region has 3 Hv regions which are arranged as a flat surface that
contacts amino acid residues of MHC molecules and peptide antigens
TCrs exist as αβ chains (most common, MHC restricted and responsible for CD4+ and CD8+ cells) or γδ
chain (rare and not MHC restricted). Unlike Ig, TCrs use both V domains for binding sites, use fewer C
regions and has 3 heavy chain V regions arranged in a flat surface.
Similarities to Ig:
● The overall structure of TCR is similar to the membrane-bound

antigen-binding fragment of Ig.
● The domains farthest away from the membrane are similar to Ig variable
How are TCR and Ig region domains and the domain closest to the membrane is similar to Ig
similar? constant region.
● The 3-dimensional structure of the extracellular portion of the TCR is

similar to that of Ig
● Gene segments are also similar: the α and γ chains are like the genes for
Ig κ and λ light chains in that they use only V and J segments. The genes
for the β and δ chains are like Ig heavy chain genes, as they use V, D, and
J gene segments.
● Genetic Mechanisms are also similar, except TCR remains the same after
antigen stimulation. There is no somatic hypermutation.
TCR is similar to membrane-bound Ig and the domains farthest away from the membrane are similar to Ig
variable region domains and the closest to the Ig constant region. The 3-dimensional structure is also
similar to Ig. The gene segments like α and γ chains are similar to Ig’s β and δ chains and the
nonantigen-dependent genetic mechanisms for diversity are similar.
Describe alpha chain α TCR Chain:

synthesis and
organization.
Synthesis:
● Somatic recombination and DNA rearrangement occur between the V and
J gene segments to form the V region exon.
● V region and Cα region are transcribed to primary RNA Transcript
● RNA splices into mRNA; mRNA is translated to a TCR α-chain protein.
Organization:
Alpha chain is located on chromosome 14.
Alpha chain is organized on chromosome 14 and where recombination of V and J occurs to create V
region exon then the V and C regions are transcribed into RNA and spliced into mRNA then translated to
the alpha chain protein.
Chapter 7: The TCell Receptor
Describe beta chain β TCR

synthesis and
organization.
Synthesis:
● First a D and a J segment are joined and the produced DJ unit is joined to
a V gene segment.
● The complete V region exon is transcribed along with C to form a primary
RNA transcript.
● RNA splices into mRNA; mRNA is translated to a TCR β-chain protein.
Organization:
Beta chain is located on chromosome 7.
*Both chains are translated in the Rough ER an are processed through the ER and
golgi apparatus before expression at the cell surface.
Beta chain is organized on chromosome 7 and is synthesized recombination to produce DJ then VDJ
recombination. The rearranged chain is transcribed into RNA then splinced into mRNA and translated to
the beta chain protein.
Both chains are processed in the ER then expressed at the cell surface.
How do TCRs create T Cell Receptors create diversity using:

diversity? ● Germline and Combinatorial Diversity: TCR has multiple genes and a
Describe the random combination of genes.
processes.
● Junctional Diversity: This is created by the imprecise joining and addition
of nucleotides by the terminal deoxynucleotidyl transferase enzyme. T cell
repertoire can be as high as 10^16 to 10^18, and much of it contributes to
junctional diversity.
● No Somatic Hypermutation: Despite not having somatic hypermutation,
T cell repertoire size is similar to that of a B cell due to high junctional
diversity which offsets the lack of somatic mutation.
For example, there are 10 times as many J segments available for TCR α
chains as for the Ig κ and λ light chains.
TCR Antigen Recognition:
TCRs are not secreted. After antigen processing, antigens are displayed in the
Describe the MHC groove for recognition and binding to TCR. This creates an immunologic
immunologic synapse.
synapse. *Superantigens can activate T cells independent of processing and
presenting. They bind simultaneously to MHC class II molecules and to
certain TCR with particular beta chains to activate all T cells bearing this V
What is toxic shock region causing a massive immune response called toxic shock due to the
syndrome and how high release of cytokines causing low blood pressure and multiorgan
does it occur? failure.
TCRs use germline and combinatorial diversity (multiple genes in random combinations) and junctional
diversity (using enzymes to add nucleotides). They lack hypermutation and are activated by
superantigens (which causes toxic shock).
Chapter 7: The TCell Receptor
What are the In addition to MHC, T Cell requires accessory molecules to aid in recognition and
accessory molecules binding.
used in TCR Synapse and CD3
binding?
● Immunologic synapse is a two-way communication that T Cells use to
Describe the role of communicate with other cells. It is transient/lasts only for the TCell response.
the immunologic ● The TCR, however, cannot function as a receptor without the CD3 complex
synapse. which consists of four transmembrane protein chains γ, δ, ε, and ζ (zeta). CD3
molecules allow T cell activating by transducing signals to the cytoplasm after
the TCR binds antigen.
Integrins:
Describe the role of ● Integrins like leukocytes function-associated antigen I (CD11a or LFA-I)
integrins. function in adhesion and in signal transduction
T Helpers:
Describe the role of
T Helpers. T cells that carry CD4/T helper cells since they usually promote the responsiveness of
other cells:
● Tregs (regulatory T cells) is a subset of T helpers which inhibits other T cells.
● T cells that carry CD8 are called cytotoxic T lymphocytes (CTLs) and have
killing functions as inducing apoptosis of vitally infected cells.
CD4 and CD8

CD4 and CD8 are the most important which enhanced the response of specific T cells
Describe the role of
by:
CD4 and CD8.
● Stabilizing the TCR peptide MHC complex by binding to the class II or class I
MHC
● By bringing a tyrosine kinase into the proximity of the cytoplasmic tails of CD3
and zeta proteins which facilitated
Accessory molecules used in conjunction with TCRs are synapse/CD3 which facilitates cell
communication, integrins for cell adhesion, T Helpers/Tregs that inhibit or promote particular processes
and CD4/CD8 which enhance T Cell response.
Chapter 8: Major Histocompatibility Complex
What is major Major Histocompatibility Complex, in humans called Human Leukocyte

histocompatibility Antigen, is a region of DNA (chromosome 6) that encodes the antigen recognition
complex? Describe HLA molecules using their HLA genes.
its organization.
There are Class 1 (A, B, C) and Class 2 (DP, DQ, DR) MHC molecules. Class 1
How do the MHC molecules are on all nucleated cells (for intracellular pathogens) but Class 2
Classes differ? molecules are on APCs (for extracellular pathogens).
MHC is polymorphic and polygenic but lacks genetic recombination since the
chromosome 6 regions have little genetic crossovers. Thus, haplotypes (blocks of
Describe the genetic alleles) within the MHC genome are identical to their paternal and maternal
diversity of MHC.
origins. The alleles also differ in 10 to 20 amino residues.
How does it differ to
TCRs and BCRs.
Unlike BCRs and TCRs which use allelic exclusion, MHC are codominantly
expressed so any paternal and maternal alleles an individual inherits are
expressed as their MHC. An individual expresses 6 different Class 1 molecules
and 8 different Class 2 molecules.
MHC or HLA is a region of genes on chromosome 6 that encodes the receptors MHC Class 1 (HLA-A, B,
C used for intracellular antigens) and MHC Class 2 (HLA-DP, DQ, DR used for extracellular pathogens).
They are polymorphic and polygenic without recombination and do not use allelic exclusion so maternal
and paternal genes are expressed resulting in 6 different Class 1 molecules and 8 different Class 2
molecules.
What are the class 1 Class 1 MHC molecules

MHC molecules? ● They are noncovalent heterodimers of transmembrane glycoproteins: β
Describe their chain (45k weight, encoded on MHC) and β2 microglobulin (16k weight,
features.
encoded on chromosome 16).
● They are HLA -A, -B, -C and their alleles which are structurally
homologous because they share similar sequences.
● They bind peptides of 8 to 11 amino acid residues but binding depends on

the presence of anchor residues (certain amino acids) at certain positions
than the peptide sequence.
α chain:
● It forms a membrane-spanning chain of α1, α2 & α3 and contains
Describe the main polymorphic amino residues so HLA alleles encode different amino acid
structures and sequences.
features of MHC ● α1 and α2 are responsible for the α Helical region peptide-binding groove.
Class 1 molecules.
Polymorphism allows it to bind to various peptide antigens.
How does antigen ● β-pleated sheet supports the helical binding site.
binding work for MC
Class 1 molecules? β2 microglobulin
● β2 microglobulin is A nonpolymorphic, soluble protein used in every
molecule without any variation. It is needed for the folding and expression
of MHC Class 1 molecules.
● β2 microglobulin and α3 together form a domain similar to Ig during
synthesis in the Endoplasmic Reticulum which is why MHC is part of the
IgSF.
MHC Class 1 are heterodimers of the transmembrane glycoproteins: alpha chain (encoded on MHC) and
beta2 microglobulin chain (encoded on chromosome 16). They consist of HLA-A, -B and -C and bind to
peptide antigens of 8 to 11 residues. The alpha3 and microglobulin chain forms the Ig-like domain and
alpha 1 and 2 form the binding groove.
Class 2 MHC Molecules

What are the class 2 They are also noncovalent heterodimers of transmembrane proteins however both
MHC molecules? chains, α chain (33k) and β-chain (29k) are encoded in the MHC. Both are
Describe their
polymorphic. Both classes of MHC have an exon-intron structure of eukaryotic
features.
membrane proteins without any variable or constant region.
● α1 chain and β1 chain make the peptide binding groove which is the
Describe the main
structures and diverse/polymorphic region. It binds peptides of 9 to 30 residues and the
features of MHC binding is dependent on the presence of anchor residues at particular
Class 2 molecules. positions.
How does antigen ● β-pleated sheet platform structure supports the β helical binding site.
binding work for MC
Class 2 molecules?
● α2 chain and β2 make the IgSF domain (domain similar to Ig).
MHC Class 2 are heterodimers of transmembrane glycoproteins: an alpha chain and beta chain, both
encoded on the MHC. It consists of HLA-DP, -DQ and DR which binds to peptide antigens of 9 to 30
residues. The alpha1 and beta1 chains form the binding groove which is supported by the beta sheet. The
alpha2 and beta2 chains form the Ig-like domain. MHC Class 1 & 2 have the typical eukaryotic
exon-intron structure without V and C regions.
Antigen Recognition and Restriction:

It is unlikely that an antigen would have peptides that are all unrecognizable to
MHC Molecules. MHC should recognize at least one peptide. Should there be no
recognition at all, the individual has low responsiveness or nonresponsiveness to
that antigen. If MHC cannot recognize the antigen then the T Cell immune
response cannot be initiated.
How does MHC ● MHC acts as a binding site for peptide antigens/anchor residues and a
recognition affect T ligand for TCR. Part of the residues are held in the MHC groove and part
Cell restriction? juts out into the TCR binding site. TCR can only identify foreign antigen
Describe their
that is specific for it and is presented by a self-MHC. It will not recognize
relationship.
nonself MHC or foreign antigens it has no specificity for.
How does TCR ● TCR's specificity for self MHC is determined during development in the
specificity/restriction thymus where they undergo positive-negative selection which allows T
occur? Cells recognizing self MHC to survive and T Cells unable to recognize self
MHC are destroyed.
Describe the
immunologic The relationship between MHC and a peptide antigen creates the MHC-antigen
synapse and complex and the relationship between the MHC-antigen complex and the TCR
receptor-ligand creates an immunologic synapse.
relationship between
MHC and T Cells
An individual is nonresponsive to a peptide antigen if their MHC molecules cannot detect it and they
cannot initiate a T Cell immune response. This is because T Cells are specific for and restricted by self
MHC molecules. They undergo positive-negative selection based on recognizing MHC. MHC molecules
bind with peptide antigens and form a complex that binds to TCRs to create an immunologic synapse.
MHC Organization:
*LMP and TAP are used in antigen processing. Class 3 MHC is not discussed as
much of its functions are still unknown in regards to immunity but so far, they are
seen as complement.
Advantages and Disadvantages of MHC Polymorphism:

How does Polymorphism and heterozygosity mean multiple HLA genes available therefore
polymorphism affect there are multiple different MHC molecules available to present a variety of
immunity?
peptides to T Cells.
● This provides a selective advantage to a population and an individual.
Rarity in HLA genes is also advantageous. Similarly, homozygosity is
disadvantageous to an individual/population.
● Possession of certain HLA alleles/haplotypes correlates with particular

inflammatory and autoimmune diseases either due to another gene linkage
or their role in antigen processing and presentation.
What are some
diseases associated For example; HLA-A3 correlates with hemochromatosis. Likewise, B8 and DR3 -
with different HLA Addison disease, DR5- Hashimoto thyroiditis, DR2- Systemic lupus, Multiple
alleles?
sclerosis, Goodpasture syndrome and B27- Ankylosing spondylitis.
Polymorphism provides heterozygosity to MHC which allows multiple HLA genes to encode a variety of
MHC molecules that can present a wide range of peptides. Homozygosity limits the MHC variety. Certain
Inheritance of certain HLA alleles can confer particular diseases that are inflammatory and autoimmune.
Chapter 9: Review of Antigen Recognition
The Adaptive Immune system relies on genes that encode the

What are the immune cell antigen-recognition molecules or “Antigen Receptors” used in adaptive
antigen receptors involved in immune responses:
adaptive immunity? Describe
● Antibodies/Immunoglobulins (Igs)
their variations.
IgG, IgM, IgA, IgD, IgE from B Cells which use somatic
recombination of gene segments, somatic hypermutation, and
class switching to create the Ig repertoire
● T Cell Receptors (TCRs) from T Cells

From T Cells which create receptor diversity using somatic
recombination
● Major Histocompatibility Complex (MHCs)

MHC Class 1 (HLA -A, -B, -C created by polymorphism) and
MHC Class 2 molecules are both used by Antigen Presenting
Cells (APCs)
General Structure of Antigen Receptors:

Describe the general structure ● Polypeptide Chain: Made of 110 amino acid residues
of an antigen receptor. ● Immunoglobulin Domain: The chain is folded into an
antiparallel/sandwich beta-pleated sheet which is held together
by RSSR (disulfide) bonds
● Extended Structure: It facilitates the ligand-receptor pair (lock
and key structure) and creates an immunologic synapse between
antigen receptor cell/lymphocyte and APC.
All antigen recognition molecules, as well as killer cell

How can a recognition immunoglobulin-like receptors (KIRs), CD4 and CD8 share this structure
molecule become part of the so they are collectively called the immunoglobulin Superfamily (IgSF).
IgSF?
What are some common
molecules of this family?
Antigen Receptors are Igs, TCRs and MHCs. For diversity MHC uses polymorphism, Ig uses somatic
recombination and hypermutation but TCR uses somatic recombination only. They all share the general
structure of: polypeptide chain + immunoglobulin domain + extended structure and all molecules that
share the Immunoglobulin domain are a part of the IgSF.
Chapter 9: Review of Antigen Recognition
How is receptor diversity Before antigen exposure, both Igs and TCRs generate diversity using:
created? Describe each ● Multiple Combinations of Chains: light/heavy chains, alpha/beta
process. chains
● Somatic Recombination of Gene Segments: done by V(D)J
What are the enzymes
involved in Ig and TCR recombinase such as RAG1 & RAG2
diversity? ● Multiple V region Segments
● Junctional variability: done by Terminal deoxynucleotidyl
Transferase
In response to antigen exposure, Igs improve their binding affinity by

somatic hypermutation and class-switching after encountering antigens
whereas T Cells remain the same.
How does antigen exposure Likewise, MHCs also remain the same -they are always polymorphic and
affect this? polygenic. This means there are multiple copies of MHC genes present
(HLA-A, HLA-B, HLA-C) and multiple alleles (variants) of that gene at a
locus.
Ig and TCR binding sites:

● Igs binding sites vary in shape which reflects the way they
directly bind to their antigen; their ligand is antigen alone.
Describe the binding site of ● TCRs have flat binding sites which reflect the way they interact
each receptor. How does this with peptide antigens presented by MHC so their ligand is a
affect their binding peptide antigen-MHC molecule complex.
affinity/nature?
MHCs have peptide-binding grooves from the alpha-helical regions of
Describe the differing binding their polymorphic domains.
sites of MHC. ● MHC Class 2 molecules have open-ended binding sites that
allow larger peptides (9 to 30 residues) to hang over the groove.
● MHC Class 1 molecules have close-ended binding sites that
allow a fixed peptide size of 8-11 residues.
Ig and TCR use pre-antigen exposure diversity through somatic recombination, multiple v regions,
junctional variability and multiple chain combinations but only Igs use post-antigen exposure diversity
through class switching and somatic hypermutation. MHCs remain polymorphic and polygenic before and
after antigen exposure.
Igs use variable binding sites to bind directly to antigens to create antigen only ligand, T Cells use flat
sites to bind with antigens via an MHC to create an antigen-MHC ligand, MHC polymorphic grooves bind
according to open endings (long peptides by Class 2) or close ended (fixed peptides by Class 1).
Chapter 10: Antigen Processing and Presentation
What is the role of adaptive In response to antigens escaping innate immunity (first defense), the
immune response? adaptive immune system (second defense) releases a small amount of
B Cells and T cells to prevent further invasion
How do B cell and T Cell B Cells bind to antigens directly but T Cells only recognize processed
interactions with antigens
antigens presented by antigen-presenting cells (APCs) or target cells.
differ? Describe T Cells
requirements for antigen So T Cells require 2 functions:
binding. ● Antigen Processing; The mechanism by which antigens are
broken down into peptides to be presented by MHC to T Cells
● Antigen Presenting; Mechanism by which APCs or target cells

How do T Cells respond to
use either MHC Class 1 or Class 2 molecules to present antigen
antigens that are not
processed and presented? peptides to T Cells which activates them (causing proliferation).
The class of MHC used is not dependent on the antigen itself; it depends
on the intracellular pathway antigens taken within the cell during
processing and what cell is doing the processing.
● APCs are macrophages, B Cells and dendritic cells that
What are APCs and how do endocytose extracellular antigens (exogenous antigens
they interact with T Cells
generated in the cell endosome), process them into peptides
during an immune response?
then present them to T Helper Cells (CD4+) via MHC Class 2
molecules. Thus CD4 Cells are MHC class 2 restricted and are
able to detect pathogens in the extracellular environment of cells.
● Target cells are any nucleated cell (or malignant cell) infected
What are target cells and how with intracellular antigens (endogenous antigens generated in
do they interact with T Cells
cell cytosol). The pathogen/tumour is processed into peptide
during an immune response?
antigens and presented to cytotoxic T Cells (CD8) by MHC Class
1 molecules. Thus CD8 Cells are MHC Class 1 restricted and are
able to detect intracellular pathogens within cells.
*Some extracellular pathogens can live inside the cell, for example,
mycobacterium tuberculosis but are still considered extracellular.
Adaptive immunity is triggered by innate immunity failure causing a release of B & T Cells. B cells bind
antigen directly but T Cells require antigen processed into peptides and presented by APCs (B Cells,
dendritic cells, macrophages) and target cells in order to bind.
APCs process extracellular antigens in their endosome then present them to CD4+ T Cells using MHC
Class 2 molecules. Target cells process intracellular antigens in their cytosol and present them to
cytotoxic T Cells via MHC Class 1 molecules.
Describe the entire

process of antigen
processing and
1. Extracellular proteins are taken into the cell; soluble antigens are endocytosed
presentation via
MHC Class 2 by B cells and pathogens are phagocytosed by macrophages.
pathway.
2. Antigens are held in acidic endosomes which fuse with lysosome to proteolyse
antigens into peptides of 9-30 residues.
3. MHC Class 2 molecules made in the ER are protected by invariant chains

How does the APC
(membrane protein that prevents false binding) and moved to the fused endosome via
involved affect the T
Cells? a golgi vesicle. The lysosomal proteases that proteolyse the peptides now proteolyse
the invariant chain so the peptides can bind to the MHC Class 2 groove.
What T Cells
correspond with this 4. Endosome vesicle with antigen-MHC complex travels exosomal pathway then
pathway? fuses with the APC membrane to be presented to T Cells (which activates them).
What function gives If macrophages are the APC then the activated T Cells release cytokines which trigger
these T Cells their macrophage into destroying the pathogen. If the APC is a B Cell, the activated T Cells
name? trigger B Cells to make antibodies (which is why they are called T Helper Cells CD4+).
Antigens are taken from the extracellular environment into an APC, processed into peptides by lysosomal
protease in an acidic endosome, fused with Golgi holding protected MHC Class 2 molecules, bound to the
MHC molecules then transported to the cell membrane where it is subsequently fused and presented to a T
Cell. If the APC is a macrophage, T Cells release cytokines so the macrophage can destroy the pathogen. If
APC is B Cell, T Cells release cytokines so B Cell can secrete Igs.
Describe the entire

process of antigen
processing and
presentation via
MHC Class 1
1-2. Antigens from viral/cytosolic proteins are generated in the cytosol and
pathway.
digested/proteolyzed by the proteasome into peptides of 8-11 residues.
Proteolysis increases Proteasome is a protease complex from LMP gene in MHC that is increasingly
during infections. transcripted during infections to release cytokine interferon γ ( IFN-γ).
Why is this?
3.The peptides pass through the lumen and membrane of the ER via the
transporter associated with antigen presentation (TAP) to bind with the MHC
Class 1 molecules being synthesized there.
Once bound to an antigen, MHC molecules complete their formation (without
antigens, they’ll fold incorrectly).
What T Cells 4. MHC Class 1 molecules with bound peptides exit the ER via a golgi vesicle and
correspond with this fuses with the target cell’s membrane to be presented to the T Cell.
pathway?
T Cells will then either suppress intracellular infection, induce apoptosis or induce
What function gives
these T Cells their cell lysis (which is why they are cytotoxic T Cells CD8+)
name?
Intracellular antigens in the cytosol are broken down into peptides by proteasome then enter the ER via TAP to
bind to MHC Class 1 molecules and finish their formation. These MHC-bound antigens exit the ER and fuse
with the target cell’s surface to be presented to T Cells. The T cells either suppress the infection in the target
cell, induce apoptosis or induce cell lysis.
Describe the T Cells recognize linear epitopes (continuous specific amino acid sequences)
differences in T Cell because they interact with peptides presented by MHC.
and B Cell binding to B cells recognize conformational epitopes (folded protein segments –not linear)
epitopes.
because they bind to three-dimensional shapes. T cells focus on infected
cells/abnormal cells and B Cells focus on pathogens circulating throughout the
Why do T & B Cells body/bodily fluids
not recognize normal
molecules within the Therefore, molecules (like polysaccharides, unbound/free peptides, lipids
body? and nucleic acids) that are not processed to fit into the binding groove of
MHC will not be recognized by T Cells. B Cells likewise become tolerant
during their development so they will not recognize self-antigens.
Pathogens have increased their survivability in a host T Cell by adapting to avoid

detection and presentation of their peptides by MHC:
Give an example of ● Mycobacterium tuberculosis acquired the ability to inhibit
pathogenic phagosome-lysosome fusion which inhibits their exposure to lysosomal
adaptability.
proteases and reduces the chances of them binding to MHC.
● Proteins from HSV bind to TAP and inhibit peptide transport plus it reduces
the amount of HSV to bind to MHC Class 1.
● Adenovirus inhibits MHC Class 1 transcription so there are less MHC
Class 1 molecules present.
T Cells recognize the linear epitopes of antigens presented by MHC on infected cells or APCs whereas B Cells
recognize three-dimensional epitopes from pathogens found in blood or bodily fluids. T Cells will not recognize
molecules not processed to fit into MHC and B Cells are tolerant of self-antigens. Pathogens continually adapt
to decrease being detected by MHC.
Dendritic Cells (DCs)

What are dendritic Conventional DCs (cDCs) are immune cells that reside in tissues and become
cells and their activated after infection or injury then migrate to lymph nodes to promote adaptive
subtypes?
immune responses.
Plasmacytoid DCs (pDCs) are a unique subset of dendritic cells specialized in

secreting high levels of type 1 interferons to promote antiviral immunity
● They sample the environment for extracellular antigens using their

dendritic abilities (forming and retracting) and toll-like receptors
What roles do ● They are motile and move from bone marrow to tissues then to lymph
dendritic cells play in nodes when an infection found
immune responses? ● They bridge innate and immune responses
● Since they detect extracellular antigens, they use MHC Class 2 molecules
and have very high levels of it.
● They also secrete cytokines (cDCs secrete interleukin-12 and pDCs
secrete interferon-alfa) which stimulates CD4+ T Cells
DCs are categorized into conventional which migrate to infections during immune responses and plasmacytoid
which secretes interferons during viral infections. They use MHC Class 2 molecules to capture extracellular
antigen, migrate during infections, and secrete cytokines.
Chapter 11: Lymphocyte Activation
What is signal Unlike the innate immune system which signals danger, the adaptive immune
transduction and its system triggers lymphocyte activation via signal transduction.
importance in
adaptive immune Signal transduction is the process by which molecular events of antigen
responses? recognition are translated into a cellular response:
● The antigen is recognized which produces a signal that must be

Describe the process transmitted to the cell’s interior to produce a response such as proliferation
of signal or secretion.
transduction. ● The process is very dependent on intracellular molecules to induce second
messengers and activate biochemical pathways.
● At the end of the biochemical pathways are transcription factors that
initiate new gene transcription for proliferation, division and differentiation.
B and T Cell Receptors are noncovalently linked together with other proteins and
What is a receptor they span across the cell membrane and into the cell cytoplasm but the
complex? Why is it sequences in the cytoplasm are short “tails” which are unable to reach/interface
necessary? the intracellular molecules that activate lymphocytes.
To combat this, other proteins must interact with the receptors to communicate the
signal.
The Receptor Complexes:
B Cell and T Cell receptors form a multimolecular complex which is made up of a

receptor and + invariant molecules with immunoreceptor tyrosine-based
What is ITAM’s role activation motif.
in signal
transduction? Immunoreceptor tyrosine-based activation motifs (ITAMs) are protein sequences
that are essential for signal transduction. They contain amino acid tyrosine which
is phosphorylated by protein tyrosine kinases (PTKs) during cell activation. Then
the phosphorylated ITAM interacts with signaling proteins within the cytoplasm to
pass on the activation signal.
Signal transduction takes antigen recognition and communicates it to intracellular molecules so transcription
can occur for cell proliferation, division and differentiation. The antigen recognition receptors cytoplasmic tails
are too short to induce any signals so they are coupled with other proteins and ITAM to form a complex that
can pass on the signals to the cell’s nucleus/ER.
Describe the BCR B Cell Receptor Complex:

Complex. ● Membrane-Bound Immunoglobulin (mIg) + two variant proteins Ig-alpha and
Ig-beta
● The variant proteins are a disulfide-linked heterodimeric (composed of two
different amino acid chains) complex. They are necessary for mIg expression and
signal transduction due to their large intracellular tails.
T Cell Receptor Complex:

● TCR alpha-beta or gamma–delta chains + six accessory protein chains (4 from
Describe the TCR
CD3 and 2 from zeta)
Complex.
● The accessory protein chains CD3 and zeta have large intracellular regions
containing ITAMs which helps with the signal transduction from TCR that is bound
to the MHC-peptide complex from the APC.
The BCR Complex consists of mIg and two variant proteins Ig-alpha and Ig-beta linked by disulfide bonds.
Their large tails provide the signals needed for mIg. TCR Complex consists of the alpha-beta or gamma-delta
chains plus six accessory proteins containing ITAM to help transduce signals from the TCr bound to
MHC-peptide.
B and T Cell Activation:
Both cells require primary and second (costimulatory) signals:

Describe and
compare signal For primary signals the receptor complexes must be clustered. B cells achieve this
transduction in by cross-linking of molecules by multimeric antigens. To optimize signal
activating B Cells.
transduction, B Cells cluster with the B Cell coreceptor which consists of 3
How does clustering
impact this? proteins; CD21 (complement receptor r- CR2), CD19 and CD81. This makes up a
coreceptor complex.
● Protein antigens that are bound to C3D can bind simultaneously to CD 21

and the BCR. This allows CD21, CD19 and CD81 coreceptor complexes to
cluster and cross-link with the BCR and induce phosphorylation on the tail
of CD19.
● This allows PTKs from the Src family to bind to the tail and increase the
signaling molecule concentration around the BCR which enhances the
signaling efficiency.
TCR clusters by binding to MHC-peptide complex on the APC via TCell-APC

contact. The binding and contact are facilitated by accessory/adhesion molecules
Describe and like CD11a or leukocyte function-associated antigen 1 which bind to CD54 or
compare signal intracellular adhesion molecule (ICAM-1) on the APCs.
transduction in
activating T Cells.
● Just a few hundred bound TCRs are needed to initiate the primary signal.
How does clustering
impact this? To optimize signal transduction, T Cells use CD4 and CD8 act as
coreceptor molecules; CD4 with MHC Class 2 and CD8 MHC Class 1.
When the TCR binds to the Class 2-peptide complex, the CD4 on the T
Cell also binds to the MHC Class 2 molecule.
● The tyrosine kinase Lck (an Src kinase), is associated with the cytoplasmic
part of CD4 and CD8. So Lck is localized with the TCR complex when CD4
or CD8 binds with MHC class 2 or 1 peptide complexes.
The coreceptors increase the signaling molecule concentration and reduce the
number of MHC-peptide complexes required to trigger a T Cell response.
T and B Cells are required to cluster for signal transduction. B Cells cluster with the B Cell correceptors (CD21,
CD19 and CD81) by cross-linking with antigens to make up a coreceptor complex. T Cells cluster by TCR
binding to MHC-peptide complex on the APC along with adhesion molecules on the T Cell that bind with the
APC’s adhesion molecules. The coreceptor complexes increases the signalling concentration and reduces the
complexes needed forT Cell responses.
What are the Intracellular Molecules

intracellular Intracellular molecules (PTKs) and protein tyrosine phosphatases (PTPs) form the
molecules involved link between receptor activation and activation of biochemical pathways that
in signal
amplify and transmit the signal.
transduction?
B Cells:
● When cross-linking the BCR, PTK from the Src family phosphorylate
ITAMs in the receptor protein cytoplasmic tails. This attracts other
signaling molecules to the cytoplasmic side of the receptor.
Describe intracellular
molecules' roles in T ● Another PTK called Syk binds to the phosphorylated ITAM sequences in
cells and B cells. Ig-alpha and Ig-beta and is then itself activated by phosphorylation. This
phosphorylation is done by Src family kinases or another Syk molecule
bound to an adjacent BCR chain.
What is the early
response of signaling T Cells:
during B and T cell
● The clustering of the TCR, CD3 and CD4/CD8 proteins brings the PTK
activation?
called Lck into the receptor complex upon recognition of peptides
displayed by MHC on APCs. Lck phosphorylates the ITAMs in the
cytoplasmic sequences of CD3 and zeta chains.
● This attracts PTK ZAP-70 (unique to T Cells and Natural Killer Cells but
still a part of the PTK family like Syk). Once a critical number of Syk or
PTK ZAP-70, the signal is transmitted from the membrane and is amplified
by activation of several pathways.
*Early response: up to SHP which are SRC enzymes that phosphorylate ITAMs
and trigger Syk/ZAP70
PTKs and PTPs are responsible for amplifying and transmitting the signal from the clustered BCR and TCr
complex to attract Syk in B cells and ZAP70 in T cells to bind to phosphorylated ITAM and continue the
signaling pathway.
Signaling Pathway From Membrane to Nucleus
Three main signaling pathways are used:
(PLC-γ) Pathway 1
What are the three ● Syk (in B Cells) or ZAP-70 (T Cells) is activated by cross–linking which
main signaling phosphorylates PLC-γ. This causes PLC-γ to travel to the cell membrane
pathways used? to catalyze the cleaving of phosphatidylinositol 4,5-bisphosphate (PIP2) to
Describe each of produce diacylglycerol (DAG). DAG activates the protein kinase C which
them. induces phosphorylation of several proteins necessary for activating
transcription factors like NF-κB. NF-κB is needed for T and B Cells to
express cytokines genes.
(PLC-γ) Pathway 2
● Syk (in B Cells) or ZAP-70 (T Cells) is activated by cross–linking which
phosphorylates PLC-γ. This causes PLC-γ to travel to the cell membrane
to catalyze the cleaving of phosphatidylinositol 4,5-bisphosphate (PIP2) to
produce inositol 1,4,5-trisphosphate (IP3). IP3 causes stored Ca2+ to be
released which raises cytoplasmic Ca2+ levels. This activates
calcium-dependent enzymes needed to dephosphorylate the transcription
factor NK-AT which is needed for cytokine gene expression.
RAS Pathway:
● Syk or ZAP-70 is activated by cross–linking then activates single-chain
guanosine trisphosphate (GTP)–binding proteins like RAS proteins. This
leads to signaling pathways being activated that lead through the
mitogen-activated protein (MAP) kinases directly to activation of
transcription factors like AP1 resulting in cell proliferation.
The first PLC pathway continues after Syk or ZAP70 phosphorylates PLC leading to the cleavage of PIP2 to
produce DAG which activates protein kinase C to induce proteins that activate transcription factors NF-κB for
cytokine expression. The second pathway is similar except PIP2 produces IP3 which releases stored
Ca2+ needed for dephosphorylating the transcription NK-AT for cytokine expression. The third pathway
Syk or ZAP70 activates GTP proteins like RAS which activates MAP kinases to activate transcription
factors AP1.
Responses:
● NF-AT, NF-κB, and AP-1 are necessary for gene transcription during the
What is the cell proliferation part of an immune response since the DNA needs to be
importance of the
sequenced and produced rapidly. Activating these pathways causes Ig
transcription factors
during an immune secretion in B Cells and proliferation/greater expression of cytokines in T
response? Cells.
● Manipulation of these signaling pathways is the principle of how
How do they impact immunosuppressive drugs like cyclosporine and tacrolius work (remember
medical chapter 1; organ transplant and allergies). To prevent over-proliferation of
advancement in T Cells, apoptosis or anergy occurs to terminate T Cells once the
drugs?
pathogen is eliminated and keep the body in homeostasis.
The transcription factors NF-AT, NF-κB, and AP-1 are needed for gene transcription for proliferating cells
during the immune responses as well as Ig secretion in B Cells and cytokine expression in T Cells.
Manipulation of these pathways are the basis of immunosuppressive drugs. To maintain homeostasis, T
Cells undergo apoptosis or enter anergy as to prevent over-proliferation.
Chapter 12: Hematopoiesis
Hematopoiesis is the process of blood cell formation occurring in the bone

What is marrow where hematopoietic stem cells (HSCs) are differentiated into common
Hematopoiesis? progenitor cells which further differentiate into mature blood cells. It occurs in
What are the three three stages:
stages of 1. HSCs, which are self-renewing and pluripotent cells, give rise to all types
hematopoiesis? of blood cell lineages within an adult. They do not have any
lineage-specific marker proteins, however, they have the protein CD34
(useful for stem cell transplantation).Then they are induced into
differentiation by intracellular molecules in the environment such as growth
factors (GFs), cytokines and colony-stimulating factors (CSFs) to become
What are the progenitor cells.
progenitor cells?
Give three examples 2. The myeloid-lymphoid progenitor cell at this point is beginning to commit to
of the mature cells different cell lineages. They are not pluripotent or self-renewing and they
developed from each cannot replenish stem cells. GFs induce progenitor cells to commit into a
blood cell lineage. lineage and develop into either common lymphoid progenitor cells (CLP) or
common myeloid progenitor (CMP) cells.
Hematopoiesis is
induced/mediated by
what molecules? 3. CLPs give rise to lymphoid cells (B, T, NK Cells) whereas CMPs give rise
to myeloids (erythrocytes, platelets, granulocytes, platelets). This is also
influenced by GFs, cytokines and CSFs.
Hematopoiesis is the process by which hematopoietic stem cells differentiate into myeloid-lymphoid progenitor
cells then commit to a blood cell lineage by differentiating into common lymphoid progenitor cells (CLP) or
common myeloid progenitor (CMP) cells. CLPs create lymphoid cells and CMPs create myeloids. The
entire process is induced by growth factors, cytokines and colony-stimulating factors.
Lymphoid cells generally have a large nucleus

What are lymphoid surrounded by a rim of cytoplasm or in the case of plasma cells/lymphoblasts, they have
cells? more cytoplasm, an extensive ER and a secretory capacity for antibodies.
Before they can become mature effector cells, they must undergo T lymphocyte
development, antigen receptor expression, selection, differentiation and antigen
interaction.
● T Cells are small, with a large nucleus and little cytoplasm but once stimulated by
antigens, they become lymphoblasts with more cytoplasm and organelles. T Cell
development occurs in the thymus. Thymocyte, the T Cell precursor, undergoes
Describe the types of development under the influence of cytokine interleukin-7 (IL-7) produced by
lymphoid cells nonlymphoid stromal cells in the bone marrow. T Cells become either CD4+
created.
helper cells or CD8+ cytotoxic T lymphocytes.
What are their roles
in immune
● B Cell development occurs in the bone marrow from pre-B Cells. B Cells are
responses?
small, with a large nucleus and little cytoplasm but once stimulated by antigens,
they become plasma cells with more cytoplasm and organelles. They also become
enabled to secrete their antibodies in the form of immunoglobulins.
● Natural Killers are innate immune cells also derived from CLP and share
common growth factors with other CLP such as IL-2 and IL-7. It also has a similar
cell appearance. NK cells do not have rearranged receptor genes but can kill
certain virally infected cells and some tumor cells using the receptors for
infected-cell antigens like tumor-specific antigens. They also help initiate specific
immune responses against different pathogen types, for example, they help
initiate responses of T-helper cells.
Lymphoid progenitor cells develop into lymphoid cells: B Cells, T Cells and NK Cells. T Cells mature from
thymocytes in the thymus into CD4+ or CD8+ T Cells. B Cells mature in the bone marrow from pre-B Cells into
plasma cells that secrete Igs. NK Cells are innate and used to initiate specific immune responses. Generally,
mature lymphoid cells have more cytoplasm, a larger nucleus and more organelles than their predecessor
cells.
Myeloid Cells: Growth factors and GF combinations are responsible for the
What mediates
differentiation of CMP into different lineages.
myeloid cell
For example, the GF erythropoietin stimulates erythrocyte development. Likewise the GF
differentiation?
combination granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and
Give an example.
monocyte-macrophage CSF (M—CSF) stimulate the development of the myelomonocytic
progenitor cells which induce the production of neutrophils, monocytes, macrophages and
dendritic cells (DCs).
What are Neutrophils ● Neutrophils are phagocytic, cytotoxic cells that migrate to inflamed/infected sites
and what role do in response to chemotactic forces (forces like GFs that cause directed cell
they play in immune migration).
responses? ○ They are called Polymorphonuclear neutrophils ( PMNs) because they
have nuclei with two to five lobes. They contain primary granules (loaded
with lysosomal enzymes like myeloperoxidase and elastase) and
secondary granules (containing lysozyme, collagenase).
1011 neutrophils are generated daily but each have a half-life of 6 hours.
What are Mast Cells
and what role do ● Mast Cells have large, stainable (purple) granules containing heparin and
they play in immune histamine. They express specific receptors on their surface for the Fc region of
responses?
certain Ig like FcRy and FcRe. They play a role in allergic responses by activation
through their receptors for IgE to release the granule.
GFs and GFs combinations are responsible for cell lineages derived from CMP. Neutrophils are cytotoxic cells
containing granules and are capable of phagocytosis. They migrate to infections via chemotactic forces. Mast
Cells are cells filled with granules which they release when their receptors interact with Ig Fc Regions during
an allergic response.
What are eosinophils and ● Eosinophils are phagocytic, cytotoxic cells that have a nucleus with two or
what role do they play three lobes containing specific granules with heparin, peroxidase and other
during an immune hydrolytic enzymes.
response? ○ They express Fc receptors FcRy and FcRe. They are used to combat
certain parasitic infections and parasitic worms.
What are ● Monocytes and Macrophages are the largest blood cells with a
monocytes/macrophages lobular-shaped nucleus and many granules. They express CD14, the
and what roles do they monocyte-macrophage marker protein.
play during an immune ○ Monocytes can phagocytose, have bacteriocidal activity and carry out
response? antibody-dependent cell-mediated cytotoxicity (ADCC). Monocytes
migrate from blood into tissue to become tissue macrophages such
as Kupffer cells of the liver.
○ They have a central role between innate and adaptive immunity
because of their role in antigen processing and presentation.
● Dendritic Cells are irregularly shaped cells with many branchlike processes
What are dendritic cells and have two subsets; conventional DCs (cDCs) and plasmacytoid DCs
and what role do they (pDCs) that are both derived from the same myelomonocytic progenitor cell
play during an immune as macrophages.
response?
○ DCs migrate to tissues like the skin where they become Langerhans
cells and take on a sentinel role. During infection and under cytokines
influence, they mature and migrate to lymphoid organs to present
antigens and activate T cells to help the protective adaptive immune
response development. cDCs secrete IL-12 which activates TH1 cells
and the pDCs secrete antiviral cytokine interferon-alfa.
Eosinophils are cytotoxic, phagocytic cells containing granules and Fc receptors which they use when
combatting parasitic infections/worms. Monocytes and macrophages are large phagocytic cells containing
granules, expressing CD14 and are able to carry out antibody-dependent cell-mediated cytotoxicity. They
can migrate from blood to tissue and bridge innate and adaptive immunity. Dendritic cells are irregular,
branching cells that migrate to tissues/skin during an infection and help activate T Cells using their
secretions.
Chapter 13: Organs and Tissues of the Immune System
Lymphocyte recirculation (lymphocyte

What is lymphocyte trafficking/homing) is the process by which naïve lymphocytes move from the organs of
recirculation?
lymphocyte generation to the lymphoid organs via the blood and lymphatic system
Lymphoid organs and tissues make up the immune system. They are divided into
primary lymphoid organs, secondary lymphoid organs and peripheral tissues:
● Primary lymphoid organs are the site of lymphocyte generation, from the yolk
What are the lymphoid
sac to the fetal liver and spleen then the bone marrow and thymus. In adults, it is
organs?
Describe a function of mainly bone marrow and thymus. By puberty, most lymphopoiesis is
each type of lymphoid B-lymphocyte production in the marrow of flat bones like the sternum, vertebrae
organ. and pelvis.
● Secondary lymphoid organs are the site of lymphocyte maturity and clonal
expansion upon contact with foreign antigens. These organs are the spleen and
lymph nodes.
● Peripheral tissues are part of secondary lymphoid organs and include

mucosa-associated lymphoid tissue (MALT) and skin-associated lymphoid tissue
(SALT). MALT lines the respiratory, gastrointestinal and reproductive tracts, and
the cutaneous (skin)immune system is lined with SALT. It traps antigens that
enter the body.
What is meant by Although lymphocytes can be distributed to all tissues (so almost all tissues can be
immune privilege? considered lymphoid), there are tissues within the eye, testes, placenta and brain that
are immunologically privileged meaning they do not have lymphoid cells so their immune
responses are limited. The most important sites of lymphocyte dispersal/distribution to
the spleen, lymph nodes, MALT and skin/SALT.
Lymphocyte recirculation is the process of naive lymphocyte movement throughout lymphoid organs and the body
via the lymphatic system and blood vessels. The lymphoid organs are primary (thymus and bone marrow),
secondary (spleen and lymph nodes) and peripheral (MALT and skin), where secondary and peripheral are sites of
lymphoid dispersal. The brain, eyes, testes and placenta rarely receive immune responses (immune privilege).
Thymus
What is the thymus? It is a bilobed organ found between the lungs and behind the sternum (the
anterior mediastinum area).
It is derived of epithelial, dendritic, mesenchymal and endothelial cells
from the third pharyngeal pouch, the corresponding brachial clefts and
the pharyngeal arch. It grows in utero until puberty then undergoes
progressive shrinking/involution at adulthood where it becomes adipose
tissue with little lymphoid tissue.
What is the cellular It consists of three main areas:
organization of this ● Subcapsular zone where progenitor T Cells are located
organ? ● Cortex where positive and negative selection occurs
● Medulla mature T cells that survived selection and are about to enter
peripheral tissues located here.
The thymus is the site of positive selection where T cells that recognize MHC
molecules receive survival signals and T Cells that recognize self-antigens must
undergo apoptosis. This leads to the survival of CD8+ and CD4+ T cells that
What is the thymus recognize MHC Class molecules.
role in lymphocyte ● It is also the site of negative selection where TCRs that bind too strongly
development? to MHC molecules or that recognize self antigens undergo apoptosis
because they cause self-recognition which leads to autoimmunity.
● *The processes are mediated by a network of epithelial cells and APCS.

T Cells that survive these processes are allowed to mature and
participate in the immune response.
The thymus is a bilobed organ and is the site of progenitor T Cells and T cell development, including the
positive and negative selection stages. It consists of the subcapsular zone, cortex and medulla.
What is the cellular

organization of this
organ?
Bone Marrow
What is the bone It is the major site of hematopoiesis which is responsible for all blood cell lineage
marrow and its role in
generation.
lymphocyte
development?
● T and B cell generation occurs within internal cavities of the bone marrow
where the B Cells and T cells develop but B cells develop from progenitor
to immature in a radial direction towards the bone’s center whereas T
cells migrate to the thymus to mature.
The bone marrow is the site of all blood cell lineage generation in the internal cavities then progresses
radially (B Cells) or to other lymphoid organs like the thymus (T Cells).
What are the lymph Lymph Nodes

nodes and its role in Small, bean-shaped clusters of cells located where blood and lymph vessels
immune responses? Converge and antigens-lymphocyte interactions occur.
Each lymph node has several areas:

organization of this ● The cortex which is the site of B cells and spherical follicles of b cells
organ? called the primary follicles. Once they are activated and start proliferating,
they produce a germinal center and become secondary follicles.
● The paracortex holds CD4+ T cells. Specialized high endothelial venules
(HEVs) are located here and are responsible for lymphocyte circulation
and trafficking.
This area is also where the dendritic cells of lymph that use MHC
molecules present antigens to CD4+ T Cells that can recognize it
to create a temporary immunologic synapse.CD4+ T cells will
then proliferate in response which enlarges this area or migrate to
germinal centers to provide help to B Cells.
● The medulla holds B Cells, T cells and macrophages.
Lymph nodes are the site of blood and lymph convergence and antigen-lymphocyte interactions. It
consists of the cortex filled of primary and secondary follicles, a paracortex of CD4+ T cells and high
endothelial venules and a medulla holding T Cells, B Cells and macrophages.
List the names and The lymph nodes are named based on their location in the body:
locations of some ● Axillary lymph nodes are located at the armpits (axilla is the anatomical
lymph nodes. term for armpit)
● Cervical lymph nodes at the neck
● Supraclavicular Lymph nodes at the clavicle (collarbone)
● Inguinal lymph nodes at the groin
● Mediastinal lymph nodes at the center of the chest (mediastinum area)
● Retroperitoneal lymph nodes behind the abdomen wall tissues
● Mesenteric lymph nodes at the abdomen/intestine region
● Pelvic lymph nodes -lower abdomen/pelvic region
What physiological Lymph nodes are the site of antigen-lymphocyte interactions and lymphocyte
changes occur in the active proliferation.
lymph nodes during ● Antigens enter in the lymph solutions or suspended particles traveling via
an infection? lymphatic vessels of peripheral tissues and are filtered out into the B
Cells within the primary follicles.
Lymphocyte activation causes lymph node enlargement due to cell proliferation
Why are lymph nodes
and fluid accumulation.
described as a filter?
● This is why lymph node areas often get swollen when someone is
infected according to the site of their infection. In the case of a
generalized infection, lymphadenopathy (general swelling) occurs. Once
the infection is neutralized, lymph nodes return to their normal size.
Lymph nodes are named according to their anatomical positions in the body. They are the site of lymphocyte active
proliferation during an infection which results in lymph node enlarging and swelling. The swelling leaves once the
infection is neutralized. Antigens in lymph fluid travel into the nodes by lymphatic vessels to be filtered by B cells in
the primary follicles.
Spleen
What is the spleen It is a major secondary lymphoid organ found in the left upper quadrant of the
and what is its role in abdomen and is usually 12cm long (a fist size) unless enlarged where it can
immune responses?
become 20cm long.
Why is it considered ● It is another site of antigen-lymphocyte interaction and lymphocyte active
a blood filter and a proliferation, however, antigens enter and leave through the blood, not
T-independent site of lymphatic vessels since the spleen is not connected to the lymphatic
antibody synthesis? system.
● It is responsible for responding to blood-borne antigens and is the source
of B cells that respond to bacterial cell wall polysaccharide antigens when
T cells are not present to help. The spleen also enlarges during infections,
usually systemic infections, blood infections, and liver diseases.
The Spleen has two main areas that correlate with its function:
● Red Pulp: where macrophages are present and in the process of filtering
organization of this
organ? the blood to remove dead red blood cells and microbes.
● White Pulp: dense lymphoid tissue where T cells are located around blood
vessels and B cells are organized into follicles, approximately 25% of total
lymphocytes in the body.
It is a lymphoid organ and a site of lymphocyte proliferation that is independent of the lymphatic system so antigens
only enter and exit through the blood. It consists of red pulp and white pulp both containing immune cells that attack
blood-borne antigens and remove microbes from the blood. It also enlarges during infections due to lymphocyte
proliferation.
MALT
This is the mucosal immune system which acts as a first line of defense by initiating
What is MALT and immune responses to antigens contacted between the mucosal surfaces (mainly
what is its cellular
gastrointestinal, respiratory and reproductive tracts) of the hosts and the
organization?
environment.
● It consists of lymphoid aggregates like the tonsils in the mucosa of the

pharynx or peyer patches in the intestine, diffuse populations of mucosal
How does it lymphocytes and cell circulation.
respond during a
microbe invasion? ● M cells are specialized cells responsible for capturing inhaled or ingested
antigens along mucous membranes via pinocytosis (cellular intake of
vacuoles, fluid, and dissolved molecules) and transporting said antigens to
encounter lymphocytes at the subepithelial tissues via transcytosis
(transcellular transport).
MALT is a form of innate barrier to microbe entry and initiates immune responses to antigens from the environment
that contact the mucous linings within the body. It has aggregates like tonsils and peyer patches containing M
lymphocytes that capture inhaled and ingested antigen using pinocytosis to transport them to lymphocytes using
transcytosis.
For example, the peyer patch in the intestine has no villi but is covered by
What is the role of follicle-associated epithelium (FAE) containing M Cells. When the M cell
FAE in an immune encounters an antigen, it transports it to follicular areas where B & T cells are
response?
present.
FAE contains lymphoid follicles underneath its surface which produces a germinal
center in response to infection.
● The B cells within the follicles secrete IgA bound to the poly-Ig receptor
What happens when across the epithelial cells. This secretion is stimulated by the transforming
M Cells carry growth factor (TGF-beta) which is a cytokine that epithelial cells secrete.
antigens to But after transport, only a piece of the poly-Ig remains as a “secretory
lymphocytes?
component” to protect the IgA from degradation in the gut lumen.
● TGF-beta is responsible for oral tolerance of food-containing peptides by

suppressing the activity of T cells.
Mucosal lymphocytes:
What are the MALT within the gastrointestinal, respiratory and reproductive tracts contains large
mucosal numbers of lymphocytes responsible for protecting the host against gut bacterial
lymphocytes and infections such as;
their roles?
● Lamina propria lymphocytes (namely plasma cells and cytotoxic
T-lymphocytes) as within the body
● Intraepithelial lymphocytes are unique to the body and 90% T cells
10-20% y-beta T cells
FAE replaces villi in the lymphoid aggregate in the intestine and contains M Cells. When M Cells transport antigens
to lymphocytes, the B cells secrete IgA with poly-Ig under the control of TGF-beta. A piece of poly-Ig is retained to
protect IgA as it goes across the epithelial cells in the gut lumen. Other lymphocytes like lamina propria and
intraepithelial lymphocytes protect mucous membranes.
SALT
● This is the major cutaneous barrier and site of interaction between the
What is SALT and its external environment and the host’s immune system.
role in immune
● It is a peripheral organ containing APCs, accessory cells like dendritic
responses?
cells (Langerhans cells –antigen-presenting DCs that phagocytose,
process and present antigens) responsible for infection via antigens
piercing the barrier. Langerhans cells migrate through lymphatics to
lymph nodes to present the antigens to T cells.
What is its cellular

organization?
● The epidermis of the skin consists of epidermal Langerhans cells and

Intraepidermal T cells are CD8+ T cells with a very high frequency of
carrying γδ TCR.
● The T cells are restricted to specific frequently occurring pathogens
whose mode of entry is the skin. The dermis of the skin consists of
macrophages and dermal T Cells.
SALT is a cutaneous barrier between the external world and the immune system. It contains a variety of
lymphocytes and APCs within its layers: the epidermis has Langerhans cells and T Cells, the dermis has dendritic
cells, macrophages, B Cells and white blood cells. The T cells are restricted to pathogens that enter through the
skin.
What is lymphocyte Lymphocyte Trafficking refers to the circulating movement of leukocytes around
trafficking? the body and is comprised of six functional elements:
Recirculation
● Mature lymphocytes circulate the body via the bloodstream and
lymphatics from blood to the tissue to the lymphatic system and the blood
again. This is done multiple times and is necessary to ensure antigens
Describe the process are encountered and bombarded by a sufficient amount of lymphocytes
of lymphocyte ● Naïve T lymphocytes circulate secondary lymphoid organs to increase
recirculation. their chances of encountering an APC with an antigen in order to be
activated.
● Effector T lymphocytes or Memory T cells retain “memory” of previously
encountered antigens so their immune responses are faster. The memory
T cells are attracted to inflamed tissues and circulate to these tissues of
the same type.
*For example, T cell's exposure to MALT causes it to recirculate or
“traffic” to other mucous tissues.
Their ability to circulate to different tissues depends on their cell adhesion
molecule (CAM) expression. CAM consists of many families such as
selectins, addressins and integrins. The T effector cells that are
positioned in peripheral tissues increase the chances of effective
protection by a secondary immune response.
*This process of trafficking is the basis of mucosal vaccination
Mature lymphocytes regularly circulate the body from the bloodstream and lymph vessels then to the tissue and
lymphatic system then back to the blood to encounter any possible pathogenic antigens within the body. Naive
lymphocytes circulate secondary lymphoid organs to increase their chances of encountering an antigen or an MHC
presenting an antigen. Memory lymphocytes readily circulate to areas where they retained info of previous antigen
encounters. Circulation depends on CAM and the position of circulating cells affect immune responses.
*Recirculation
Homing
This is a receptor-ligand regulated process by which lymphocytes differentially migrate to

What is homing and specific tissues based on their CAM:
its role in an immune ● Naïve T lymphocytes and the lining of HEVs form a receptor-ligand pair between
response? the L-selectin expressed by the T lymphocytes and the GLYCAM1 addressin
molecule expressed in the lining of HEVs. The L-selectin recognizes and binds to
GLYCAM1 in lymph nodes.
● Effector lymphocytes form a receptor-ligand bond between the integrin α4/β6

expressed by the effector cell and the MADCAM1 on the epithelium in the mucosa.
The integrin recognizes and binds to MADCAM1 to promote homing into the gut.
Homing is what causes lymphocytes to be attracted to inflamed and infected sites. The L selectin of T lymphocytes
and GLYCAM as well as α4/β6 expressed by the effector lymphocytes and the MADCAM1 causes homing.
What is Extravasation
Extravasation? This is the process by which leukocytes exit the circulatory system, enter sites of
infection then reenter the circulatory system.
The entire process occurs within seconds and is dependent on homing
(receptor-addressin interactions), not antigen specificity. This means, that in an
immune response, chemokines and cytokines attract lots of lymphocytes, some
of which may not be specific for the antigens of that infection.
Lymohocyte extravasation occurs in 5 steps:

1- Primary adhesion to endothelium
Initially, the lymphocytes flow freely across epithelial cells of the blood vessels
but are slowed by low-affinity interactions between their homing receptors and
Describe steps 1-2 in the CAM of surrounding vascular endothelial cells.
extravasation.
2- Lymphocyte activation
However, in the presence of inflammation signals such as chemokines or
cytokines, the lymphocytes are activated to create additional CAM which
promotes high-affinity interactions between the CAM of the lymphocyte and
surrounding endothelial cells.
Extravasation is the process lymphocytes leave the lymphatic system and enter infected sites. It is dependent on
homing by chemokines and cytokines. First lymphocytes flow across epithelial cells and are slowed by weak
interactions with CAM and other receptors then activated by the inflammation signals to produce more CAM and
form stronger interactions.
Describe steps 3-5 in 3- Secondary adhesion (arrest)

Extravasation. These high-affinity interactions cause the free-flowing lymphocyte to be arrested
at the site of the receptor-ligand pair and no longer flowing.
4- Diapedesis
After arrest, the lymphocyte undergoes diapedesis (cell passage via flattening,
crawling, and squeezing through cells) through tight junctions between the
endothelial cells to enter infection sites within tissues.
5- Return
Lymphocytes return to the blood via the lymphatic system.
Chemotaxis
This is a chemokine-mediated process that directs cell movement in tissues. It is
What is chemotaxis the reason why chemokines released by inflammatory macrophages at the site
and synapse of infection recruit more lymphocytes.
formation?
Synapse Formation
This is an immunologic synapse which is a junction formed between T cells and
APCs during immune responses which leads to a receptor ligand pair that
facilitates signal exchanges and T cell activation between them.
The flowing lymphocyte is arrested and undergo diapedesis where it flattens and squeezes through cell junctions to
enter infected sites, after responding, it returns to the blood via the lymphatic system. Chemotaxis refers to the
movement of cells to an inflamed or infected site under the guidance of chemokines. The synapse formation occurs
between T Cells and the MHCs/APCs during an immune response leading to cell communication through a receptor
ligand bond.
Chapter 14: B Cell Development
Describe the process B lymphocytes are continually developed within the bone marrow and undergo
of B cell development negative selection before maturing and then entering the periphery lymphoid
in the Bone marrow? organs to be activated and differentiated into antibody-producing cells.
If the B Cell does not encounter an antigen, it dies within a few weeks.
(Fetal Liver) to Bone Marrow Development:
Hematopoietic stem cells differentiate into common lymphoid progenitor cells in

the fetal liver in utero then in the bone marrow after birth. The development
Describe the within the bone marrow is dependent on Growth factors in surrounding stromal
movement of stem cells within the bone marrow. Development occurs radially from the
cells from the fetal
endosteal/inner surface of the bone where the most immature cells are to the
liver to the bone
marrow? center of the marrow where more mature cells are.
What affects
development during
this time?
Bone Marrow Development progresses in stages according to the

expression/rearrangement of Ig heavy and light chain genes and
differentiation-specific molecules to create a diverse repertoire of B cell
receptors.
1. Stem Cell:
What are the
Hematopoietic cell expresses no B cell receptors at this point but is induced into
characteristics that
define the stem cell becoming a common lymphoid progenitor cell by the growth factors within its
stage? surroundings.
B Cell development begins as early as the fetal liver and continues to bone marrow where it develops from a stem
cell to a lymphoid cell as a result of growth factors in the cell surroundings. From the bonemarrow, development
occurs radially. Gene expression and rearrangement of Ig chains are parts of B Cell development at latter stages.
What are the 2. Lymphoid progenitor Cells;

characteristics that The common progenitor cells express Cluster of Differentiation 19 (CD19),
define lymphoid recombination activating genes (RAG1 & RaG2) and Terminal deoxynucleotidyl
progenitor cells?. transferase (TdT).
3. Pro B Cell Stage

What are the events Common Lymphoid progenitor cells commit to the B cell lineage and become pro B
occurring in the Pro B cells:
Cell stage? ● V(D)J recombination of heavy chain variable, diversity and joining segments
is initiated by RAG1 & RaG2. TdT is also active during recomibantion
creating junctional diversity between the rearranged gene segments.
● The Pro B cell also synthesizes proteins VpreB and λ5 to aid with heavy
chain gene rearrangement. These proteins are used to synthesize a
surrogate light chain.
● CD19 of the coreceptor complex is present at this stage and signals the
completion of V(D)J recombination.
● The purpose of this stage is to create a μ heavy chain (μH) and surrogate
light chain (ψL) which is the foundation of BCRs. (pre-BCR)
4. Pre-B Cell Stage

If the pro-B cell successfully expresses a μH, then it becomes a pre-B cell (if
What are the events unsuccessful, it undergoes apoptosis).
occurring in the Pre B ● The cell now expresses a Pre-B-cell receptor (pre-BCR) which is a receptor
Cell stage? complex made of ψL and μH chains. The pre-BCR facilitates further B cell
development as it transduces the signals required to initiate proliferation.
● This proliferation produces multiple B cells with different polypeptide chains.

The V(D)J recombinase machinery RAG1 And RAG2 rearranges the V and J
gene segments (no D) of the light into either a κ light chain, or if
unsuccessful, then a λ light chain.
The lymphoid progenitor cells commit to the B cell lineage to become Pro B Cells and at this stage, recombination of
genes for the heavy chain and surrogate light chains. If the chain is successfully expressed, it is a pre-BCR and the
B cell is now a Pre-B Cell. The Pre BCR transduces signals to encourage proliferation of B cells which produce
varying polypeptide chains that are oranized into different complete light chains.
What occurs during 5. Immature B Cell:

the immature B Cell Once a light chain is successfully developed, the paired light and heavy chain forms
stage? the IgM molecule. This IgM molecule is the BCR and signifies that the B cell is now
Describe anergy. considered an immature B cell. RAG and TdT enzymes are now inactive.
● If at any time an immature B cell is presented with high doses of soluble
antigens that cannot cross-link the BCR or it cannot effectively bind to, it
enters an anergy state.
● Anergy is a state of unresponsiveness in B cells where they downregulate

IgM expression and are incapable of being activated. These B cells are not
killed and the state is reversible.
(This can be useful in preventing the production of autoantibodies which are
antibodies against self-antigens thus it promotes immune tolerance).
6. Negative selection:
Clonal deletion is the process by which B cells that strongly bind to self-antigens
undergo apoptosis or are deactivated and become anergic B cells. This
Describe the process self-reactivity is a result of recombination (as some receptors may recognize
of negative selection
self-antigens).
for B Cells.
● The purpose of this negative selection is to produce tolerant immature B
cells, which are B cells that do not become activated by self-antigens (any
macromolecule or substrate present in the bone marrow environment or
extracellular matrices).
The tolerant B cells now secrete increased levels of IgM and begin the expression of
membrane-bound IgD. This IgD is a result of heavy chain transcript undergoing
alternative splicing. This produces mature B cells with surface IgM that is
coexpressed with surface IgD.
● These mature cells then migrate to the peripheral lymphoid organs to
complete development. B cells that express their full Ig Genes but have not
What is the
importance of tolerant encountered an antigen are called Naïve B cells.
B Cells?
● They exit the bone marrow and enter the follicles of secondary lymphoid
organs via the bloodstream in order to encounter an antigen and trigger their
receptor response. If their specific antigen is not present, they reenter the
bloodstream and circulate again.
-Failure in signaling, pre-BCR expression, binding, IgM and IgD expression, and
strong binding to self leads to apoptosis.
The expressed light and heavy chain to form an IgM molecule and form an immature B Cell. The B cells undergo
negative selection where B cells that bind to self-antigens undergo apoptosis or enter anergy. If they do not, then
they become tolerant but naive B Cells and begin to express IgD, then circulate until they encounter an antigen.
Mature B Cell
To ensure B cells in the peripheral lymphoid organs are tolerant to self-antigens
in the environment, they undergo additional tolerance inhibition.
● Thymus dependent B cells become fully activated and produce
Describe and compare
T Cell dependent and antibodies, when secondary signals are provided by activated T cells
independent B cell whose TCR recognizes neighbouring APC’s MHC Class 2 and
development. presentation by follicular dendritic cells (FDCs).
● Without T cell help, B cells enter an anergy state (in the case of univalent
antigens) or undergo clonal deletion (in the case of multivalent antigens).
● Thymus-independent (T-independent) B cells are specialized B cells that

can respond to multivalent polysaccharide antigens without T-cell help.
The follicles within secondary lymphoid organs provide the site of antigen
What are FDCs and
interaction with incoming naïve B Cells, FDCs and T cells. The antigens here are
their roles in
lymphocyte collected by the spleen (blood-borne), lymph nodes (afferent lymph vessels) and
development and MALT (mucosa epithelial antigens).
antigen presenting? ● The FDCs are APCs unique to this site and do not express MHC Class 2
molecules.
● They use Fc receptors to retain Antigen-Antibody complexes on their
surface to present to B Cells. They are not developed in the bone marrow
like other DCs either but have the same networking structure in the
follicles.
Describe the feedback The mature B Cell can act as an APC itself to T cells. Once the B cell
loop between T and B encounters, recognizes and binds to its target, it internalizes the BCR-antigen
Cells. complex in order to process the antigen into peptide-MHC Class 2 complex to
present it to a T Cell.
This creates a feedback loop of T cell stimulating B cell then B cell presenting to
T cell.
B Cell maturation involves tolerance inhibition. T-dependent B cells require signals for T Cells with TCRs bound to
MHC Class 2 to be activated and produce antibodies. Otherwise, they enter anergy or undergo clonal deletion. T
independent B Cells call respond without T Cell signals. Naive B cells can encounter antigens at the follicles within
secondary lymphoid organs which are taken from other lymphoid organs and tissues. FDCs and mature B Cells are
both types of APCs but FDC are unique to the thymus and use Fc receptors, not MHC molecules.
Somatic Mutation
As previously stated, primary follicles of B cells develop germinal centers once
Describe the process they start proliferation (due to antigens and T Cells) and become secondary
of somatic mutation.
follicles. These germinal centers are made up of B cells and FDCs.
● At this point, somatic hypermutation occurs where the rearranged
variable region exons of light and heavy chains undergo single nucleotide
substitutions.
● The B cells then undergo positive selection where B cells that remain
with a high affinity for antigens receive survival signals from FDc and T
cells whereas B cells that have low affinity undergo apoptosis.
How does somatic ● This is intended to produce populations of surviving B cells with the
mutation result in highest affinity antibody which eventually leads to affinity maturation as
affinity maturation? the high-affinity B cell population continues to proliferate and undergoes
somatic mutation and antigenic selection.
Ig Class Switching
The mature B Cell has only surface IgM, surface IgD and secreted IgM but the
other classes of Ig are necessary according to the antigen encountered.
Describe the process ● Therefore, T cells must help in inducing these different forms of Igs via
of Ig class switching. class switching.
● B Cells may also leave the germinal center to differentiate into a plasma
cell which returns to the bone marrow and secretes antibodies.
● It can also differentiate into a recirculating memory B Cell which can

readily be reactivated in response to antigens and rapidly
produce/secrete antibodies.
B Cells at the secondary follicle stage undergo somatic hypermutation at the variable regions of their chains. Then
the B cells undergo positive selection where only high antigen affinity B Cells receive survival signals and low affinity
B Cells undergo apoptosis so the B Cell population constantly increases in affinity. The mature B cell with its sIgM,
surface IgM and surface IgD use the help of T Cells to switch their constant regions and become new Ig classes. It
can also become plasma cells that secrete antibodies or recirculating memory B Cells.
T1 Antigens
Describe the influence Thymus independent antigens (T1 antigens) are able to activate B cells without
of T1 antigens on the help of T cells do this by cross-linking/engaging multiple BCRs using their
immune responses.
repeated motifs. T1 B cells are found in the spleen and develop fully in late
childhood. Bacterial polysaccharides and bacterial cell wall components like
lipopolysaccharides are T1 antigens.
● T1 antigens tend to proliferate quickly and overwhelm the immune

system, especially since important T cell-mediated responses like
mutation and class switching are inactive since no T cells are involved
What abilities do T1
here.
Antigens have that
make them a threat to ● Another implicating feature of T1 antigens is that their components
immune responses? cannot be broken down into peptides so T cells are not activated by
them. This means vaccines only manage to recruit low-affinity IgM with
poor memory. Protein-conjugated polysaccharide vaccines subside this.
B1 B Cells
B1 B cells are another differentiation of immature B cells that reside in the
How do B1 B Cells
differ from peritoneum and express cell surface markers different from conventional B Cells.
conventional B Cells?
How are they ● They are replenished by cell division through carrying surface IgM in
independent? peripheral tissues rather than bone marrow renewal like conventional B
cells. The B1 cells are useful against polysaccharide antigens as their
receptors are reactive toward bacterial antigens. They have
polyspecificity (cross-reactivity for multiple antigens) and are restricted to
a few VH genes and limited insertional diversity as they lack TdT
expression
● They have the unique ability to produce Abs without Ag stimulation but
What are natural they tend to cross-react with self-antigens. These spontaneously
antibodies? produced self-reactive antibodies are natural antibodies and may give
rise to autoimmunity
● They tend to align more with innate immunity due to their lack of memory,
class switching, affinity maturation and restricted gene arrangement.
T1 antigens are independent of T cells for activation B cells and B1 B cells are independent of antigens for their
antibody production. The B1 B cells use cell division to maintain its population and are very cross-reactive with
self-antigens and may give rise to autoimmunity. They lack most of the features of conventional B cells so they are
more similar to innate cells. T1 antigens have rapid proliferation that overwhelms the immune system and they do
not have peptide components so both MHC and T Cells are not useful in combatting them.
Chapter 15: T Cell Development
T Cells must contain a diverse repertoire of TCR, be able to recognize self-MHC

What is the end result (MHC-restricted), recognize nonself antigens presented by the MHC and do not
of T Cell bind strongly with self antigens (self-tolerant).
Development?
During T Cell development in the thymus, the progenitor cells called thymocytes
undergo selection which results in most T Cell dying before maturity.
Give an overview of T ● To achieve maturity, they must undergo a double negative stage, double
Cell Development (the positive stages and single positive stages involving selection.
stages and their After birth, cell division and proliferation enable mature T Cells to continually
location). replenish their population under the influence of the growth factor, interleukin 7
(IL-7). The thymus is not necessary.
T Cell development produces self tolerant, MHC restricted T Cells through double negative, double positive and
single positive stages involving selection.
Double Negative (DN) Stage:

What events occur ● The thymocytes in the subcapsular/outer cortex region are called DN cells,
during the double meaning double negative as they are negative for both CD4 and CD8
negative stage?
surface molecules and the TCR genes are still unrearranged (germline).
● Afterwards, DN undergoes differentiation (see DN2-4) and begins

commitment to either the αβ or γδ T-cell lineage, usually the former since
the latter is not MHC restricted (and they leave the thymus at this stage).
● The TCR Gene rearrangements occur where recombination activation

genes (RAGs) and terminal deoxynucleotidyl transferase (TdT) aid in the
rearrangement of β, γ,and δ genes. If a γδ receptor is produced, a γδ
TCR-expressing T cell is produced which commits to the γδ lineage. The
same process occurs for αβ lineage (which forms the pre TCR and is more
commonly committed to).
Pre-TCR complex is necessary for signal transduction to prevent further beta chain
Why is the pre-TCR
complex important in rearrangement and promote proliferation of DP T Cells. The proliferation induces
T Cell development? alpha chain rearrangement after recombinase expression (similar to BCR complex
in B Cell development).
Double Positive (DP) Stage:

What events occur ● The DN cells move to the cortex and now express CD4 and CD8, thereby
at the double becoming DP cells. At this stage they undergo positive selection where if
positive stage? they express a TCR that recognizes self MHC, they can continue
development.
Single Positive (SP) Stage:

● DP cells migrate to the medulla and undergo negative selection where cells
What events occur that recognize self antigens are removed via clonal deletion.
at the single positive
stage? ● Then they undergo lineage commitment: Depending on what MHC Class
the TCR reacts with, the cells commit to a particular lineage: CD4- CD8+ or
CD4+ CD8-. CD4+ cells can further commit to becoming Tregs/regulatory
TCells.
At the DN stage (outer cortex), DN cells undergo differentiation into a particular lineage and gene rearrangement to
form the pre TCR complex needed for cell signalling during development. At the DP stage (cortex), the cells express
both receptors and undergo positive selection. At the SP stage (medulla) cells undergo negative selection and
further lineage commitment into either CD4+ cells (and Tregs) or CD8+ cells.
MHC and Self Peptide Roles’ in T Cell Development:

What role does
MHC presenting ● Immature T Cells are presented with antigenic peptides by MHC on cortical
self peptides play in thymic epithelia during positive selection and dendritic cells, epithelial cells &
T Cell macrophages during negative selection.
development?
● If no antigenic peptides are present, the APCs express self-peptides from
proteolytic digestion of normal cytoplasmic proteins (for MHC Class 1) or
endosomal digestion of extracellular proteins (MHC Class 2).
● Thymic medulla cells evolved to express proteins unique to other organs using
the autoimmune regulator AIRE. However, AIRE gene mutations lead to
autoimmune problems like autoimmune polyendocrinopathy candidiasis
ectodermal dysplasia (APECED).
Positive and Negative Selection in T Cell Development:
What is the ● In positive selection, the TCRs of DP cells in the cortex must successfully
importance of interact with the self-MHC of cortica thymic epthelia using medium affinity, then
positive and they are considered self-MHC restricted and allowed to continue thymic
negative selection migration to the medulla. Unsuccessful interactions/recognition of self-MHC
in T Cell
result in DP cell apoptosis.
development?
● In negative selection, the now MHC-restricted DP cells in the medulla must
successfully interact with APCs presenting self-peptides to create self-tolerant,
MHC-restricted DP cells. DP cells using high affinity for self-peptides undergo
apoptosis.
How do DP cells
● The DP cells that recognize MHC Class 1 become SP by expressing only CD8+
become SP cells?
and DP Cells that recognize MHC Class 2 become SP by expressing only
CD4+. However, some SP cells expressing CD4+ with the highest affinity
After the selection activate FOXP3 (a transcription factor) to become Tregulatory cells (nTreg).
processes, what
happens to the ● Cells that undergo apoptosis are removed by macrophages in the thymus. Most
remaining T Cell of the developing T cells undergo apoptosis since most DP cells die during the
population in positive selection and ⅔ of surviving cells die during negative selection. These
development? surviving cells are naive, mature T Cells (naive because they have not
encountered non self antigens).
MHC presents antigen peptides or self peptides (from digesting cytoplasmic or extracellular proteins) to immature T
Cells during their development. Cells like medulla thymic cells use AIRE to express unique proteins to the
developing T Cells. Positive selection induces apoptosis in T Cells that cannot recognize self-MHC whereas
negative selection induces apoptosis in T Cells that recognize self-peptides. DP cells become SP based on the class
they recognize (MHC Class 1-CD8+, MHC Class 2-CD4+).SUrviving T Cells are mature but naive.
WHat role does The Role of TCR Signaling in Selection

TCR signaling play ● Remember how the pre B cell BCR triggers signaling for B Cell
in selection? development. The TCR does the same.
Reference it to
BCR signaling. ● The TCR and MHC-peptide interactions mediate positive and negative
selection using the intracellular signals from their immunologic synapse.
● The mediation is based on the affinity of the interaction, where too high
affinity and too low affinity can lead to negative selection but medium affinity
leads to continued maturation and high affinity leds to Tregs development.
What is the
process of antigen
priming?
Why is it Antigen Priming
necessary? Naive, mature T cells migrate out of the thymus and enter the secondary lymphoid
organs where they circulate until they meet an APC presenting antigen peptides to
initiate antigen priming:
● The TCR of the T Cell recognizes their cognate antigen (the antigen they are
specific to) on the MHC to produce a primary/first signal and receive a
costimulatory signal which activates the T Cell and initiates the signaling
cascade (to trigger clonal expansion and differentiation and antigen priming).
● Activated, primed T cells are called primed effector cells which express
What are the additional adhesion and surface molecules (like CD145). The primed
outcomes of effector cells can follow 3 different functional pathways:
primed T Cells?
1. Return to germinal centers and aid in B Cell activation.
2. Circulate the peripheral organs and fight infections. Then undergoes
apoptosis once infection is neutralized (this is necessary to maintain
homeostasis).
3. Mature into memory T Cells that have a greater efficiency in fighting
re-encountered antigens.
Just like the pre BCR complex, the TCR complex interacts with MHC-peptide complex to produce signals which
mediates the development of T Cells based on the interactions affinity. Naive, mature T Cells are primed by antigens
when they circulate secondary lymphoid organs. After encountering the cognate antigen on the MHC of an APC, it
receives a primary and costimulatory signal to become effector cells. Effector cells migrate to germinal centers to
activate B Cells, circulate the periphery to fight infections or mature into memory T Cells.
What are self Self-Reactive T Cells

reactive T Cells? Self reactive T Cells are non self tolerant T cells that escaped negative selection (central
How does the tolerance). They often escape to the periphery/peripheral organs but mechanisms called
body deal with peripheral tolerance mechanisms are available to prevent them from doing harm such as:
self reactive T ● Immune-privileged sites like the eyes, brain and testes where antigens can be
Cells?
hidden.
● High Zone Toleration where T cells in the periphery undergo apoptosis after
repeated activation from high levels for a specific antigen (deletion-induced
toleration).
● Clonal anergy where T cells are inactivated due to missing components in either
their signaling cascade or in their antigen recognition (maybe an adhesion
molecule or costimulatory molecule is missing).
● Tregs cells (regulatory T cells) that are specific for self antigens parole peripheral
organs and inhibit self reactivity.
T Cell Subsets
CD4+ and CD8+ T cells are formed from successful interactions with the MHC-antigen
What are the T complex where the T Cells receive a costimulatiory signal.
Cell Subsets?
Describe their CD4+ T Cells are responsible for monitoring extracellular pathogens and the peptides
functions. displayed by MHC Class 2 molecules (digested by endosomes, taken up via
phagocytosis).
● Their subsets are THelper Cells (TH cells: TH1, TH2, TH17), T regulatory cells
(Tregs) and inducible Tregs (iTregs, cells involved in tolerance like CD4+ CD25+
FOXP3+).
● The subsets develop according to the signals within the environment and the
antigen priming. THelper cells develop in response to danger signals from innate
cells and release cytokines to aid in immune responses. Tregs develop from high
What determines
affinity interactions between DP T Cells and MHC during positive selection and
the development
of T Cell Subsets? iTregs develop from naive CD4+ T cells.
CD8+ T Cells are responsible for monitoring intracellular pathogens and the peptides
displayed by MHC Class 1 molecules (digested by proteasomes, taken up from the
cytoplasm).
Self reactive T Cells are non tolerant and often escape to the periphery, however, their functions are limited due to
the presence of immune privileged sites, regulatory T Cells, high zone toleration and clonal anergy. T Cell subsets
are developed based on the cell signaling and antigen priming. These subsets are CD8+ cells which are cytotoxic
ce;lls or effector cells and CD4+ cells which include THelper cells, TRegulatory cells and inducible regulatory T
Cells.
Chapter 16: T Cell Interactions and T Cell Help
Antigens encounter APCS through the lymphatics or at the site of infection. APCs
Where do antigens (including B cells which act as an APC) use MHC Class 2 molecules to present
encounter APCs and processed antigen peptides to T Cells.
what does it create? This causes signalling through the MHC-peptide complex and TCR activates
biochemical pathways which creates an immunologic synapse.
The immunologic synapse is a result of antigen recognition by the T Cell and is

formed by:
How s the immunologic
● Additional expression of cell adhesion molecules (CAMs) which
synapse formed?
strengthens cell adhesion
● Redistribution of molecules within the involved cells’ membranes lipid

bilayer such as transmembrane proteins
● Reshaping of the involved cells’ membranes to facilitate molecular

redistribution and migration of the receptor-liand paris to the area where
the involved cells are in closest contact. This is all done by cytoskeleton
proteins like actin filaments.
Molecules involved in the synapse are:

What are the molecules ● T Cells: TCR, CD4/CD8, lymphocyte function-associated antigen 1
involved in the (LFA-1), CD28, CD154.
immunologic synapse?
● APCs: MHC, intracellular adhesion molecule 1 (ICAM-1), CD80, CD40.
T Cell recognition of an antigen presented by MHC causes molecular rearrangement of cell membrane molecules
and receptor-ligand pairs, facilitated by the cell cytokskelton, which creates the immunologic synapse. The
molecules involved are TCR, CD4/CD8, LFA-1, CD28, CD154 from T cells and MHC, ICAM-1, CD80, CD40 from
APCs.
What is the B Cell-T B Cell-T Cell Conjugate

Cell Conjugate? When the immunologic synapse forms between a T Cell and a B Cell, both cells are
described as one unit called the B cell-T cell conjugate.
This is formed by:
● B Cell recognizing (BCR), processing and displaying (MHC 2) an antigen to
How is the conjugate
a CD4+ T Helper Cell (TH cell) so both cells are now activated
formed?
● Both activated cells form a functional connection by signaling proteins and
adhesion molecules to create a B Cell-T Cell conjugate
● The B-T conjugate develops an immunologic synapse in the area where

signaling occurs.
● Costimulatory signals from the receptor-ligand pairs in the immunologic

synapse are released
How does the T Cell The T Helper Cell in this interaction performs coordinated immune responses with
involved help B Cell the B Cells by releasing cytokines (in addition to the costimulatory signals) which
immune responses? causes B cell differentiation into plasma cells that secrete IgM.
What is the fate of B B cells that do not become plasma cells form a germinal center in the lymphoid
Cells that are not follicles where they undergo somatic hypermutation in the v gene segments, affinity
plasma cells? maturation by selection, and Ig class switching by replacing the μ heavy chain is
no with a γ, ε, or α heavy chain to produce IgG, IgE, or IgA.
TH cells in the germinal center help B Cells by:

● Expressing costimulatory pairs, C28/CD80 and CD40/CD154, which causes
What are THelper cells both B cells and T Cell to differentiate (both differentiate into memory cells)
role in Ig switching?
● Mediate B cell class switching to IgG using TH1 cytokine interferon gamma
(IFN-γ).
● Mediate B Class switching to IgE using TH2 interleukin 4 (IL-4) if there is a

worm/arthropod infection.
● If it is mucosal, the transforming growth factor beta (TGF-β) from dendritic

cells mediates switching to IgA.
● CD154 gene mutations result in IgM syndrome.
B Cells presenting antigens to T Cells results in a B-T conjugate and immunologic synapse which releases
costimulatory signals/cytokines that trigger plasma cell differentiation IgM secretion. Non plasma cells form germinal
centers and undergo differentiation, especially Ig class switching. TH cells in germinal centers mediate Ig class
switching by secreting cytokines depending on the invading pathogen.
How do TH cells help

CD8 T cells? CD4+ T Helper Cells induce CD8+ T Cells into effector CD8+ cytotoxic T Cells which
are responsible for killing cells infected by intracellular pathogens or tumor cells by
Describe the process inducing apoptosis:
of TH cells inducing
● TH cell is activated upon recognition of viral antigens presented by an APC.
CTLs.
● The antigen recognition causes a release of IL-2 and a second signal from
IL-2 receptor which activates the viral antigen-specific CD8 cells and causes
the CD8 cells to differentiate into effector CTLs.
What role do TH cells
● TH1 cells also secrete IFN-γ to stimulate CTLs.
play in an immune
response?
Innate cells (first line of defense) recognize patterns on invading pathogens and
release cytokines which trigger TH cell differentiation into TH cell subsets. Likewise,
APCs also recognize and trigger TH cell differentiation.
What determines the The TH cells then release cytokines which recruit both innate immune cells
TH subset involved in and adaptive immune cells (remember in chapter 1; cytokines connect innate
immune responses? and adaptive immunity).
TH Cell subsets (TH1, TH2 and TH17) mediate the differences in immune
responses through their interactions with other cells based on the type of invading
pathogens involved.
CD4+ T Helper cells induce CD8+ T Cells to differentiate into cytotoxic effector T cells via secretion of IL- from
antigen recognition. TH cells also release cytokines that recruit innate and adaptive cells to the source of pathogen
invasion. The TH cells used in this response are based on the type of pathogens invading and the TH cells'
interactions with nearby cells.
TH1 Cells
● They recognize intracellular pathogens like mycobacteria, viruses and
Describe the roles and
pathogens.
functions of TH1
Cells in an immune
● Macrophages or dendritic cells release IL-12 upon pathogen recognition
response.
which initiates the TH1 response.
● Activated TH1 releases IFN-y which recruits:
○ Innate Cells: Nk Cells and macrophages
○ Adaptive Cells: CTLs and B Cells with IgG
○ And has features like: antiviral properties which prevent viral

replication
● TBX21 (or Tbet) is responsible for expressing TH1 cells, their IL-12
receptors, TH1 memory and for suppressing the other subsets of TH cells.
TH1 cells are transcripted by TBX21 and they are triggered by IL-12 release upon recognition of intracellular
pathogens by macrophages and dendritic cells. TH1 cells release IFN-y which has antiviral properties and recruits
NK cells, macrophages, CTLs and IgG-secreting B plasma cells.
Describe the roles TH2 Cells

and functions of TH2 ● They recognize surface pathogens like helminths and anthropods.
Cells in an immune
response. ● It is not known what recognizes the pathogens first but they release ILs like
IL-15 and IL-13 that trigger TH2 response.
● Activated TH2 Cells release IL-4 and IL-5 which recruit:
○ Innate Cells: Mast Cells, Eosinophils, Goblet cells hyperplasia (mucus

secretion), smooth muscle hypertrophy
○ Adaptive Cells: B cells with IgE
○ And has features like: autocrine and paracrine properties
● GATA3 is the transcription factor responsible for expressing TH2 cells,

expressing IL-4 & IL-5 receptors, silencing the other receptors and TH
subsets.
TH17 Cells
Describe the roles ● They recognize extracellular pathogens like bacteria.
and functions of
TH17 cells in an ● Macrophages and dendritic cells that recognize extracellular pathogens
immune response. release IL-23 which initiates TH-17 response.
● Activated TH-17 Cells release IL-17 which recruits only innate cells;
neutrophils, and has the feature of stimulating antimicrobial peptides secretion
from epithelial cells.
● RORγt is the transcription factor responsible for TH17 cells
What is meant by TH TH Cell subsets are epigenetic meaning that they are inherited/passed on from parent
cells being T cell to daughter T cell during mitosis by changes in chromosomes without alteration
epigenetic? in DNA.
Environmental factors (pathogens) cause methylation of DNA and modification of
How do TH cells histones which increases transcription or silences transcription for particular genes in
differentiate into their the TH cell [See transcription factors of each TH subset]. In response to specific
subsets? pathogens, the daughter T cells become more polarized to a specific type of
transcription factor for that pathogen.
TH2 cells are transcripted by GATA3 and they are triggered by IL-15 and Il-13 release upon recognition of surface
pathogens. TH2 cells release IL-4 and IL-5 which has auto/paracrine properties and recruit mast cells, eosinophils,
goblet cells and IgE-secreting B plasma cells. TH17 cells are transcripted by RORyt and are triggered by IL-23 upon
recognition of extracellular pathogens by macrophages and dendritic cells. TH17 cells release IL-17 which has
antimicrobial properties and recruits neutrophils. TH subsets are epigenetic so they are inherited without DNA
changes and rely on silencing or increased transcription of particular genes.
Chapter 17: Immunologic Memory and Homeostasis
What is immunologic Long-term immunologic memory is adaptive immune cells ability to produce an
memory? enhanced immune response to previously encountered antigens.
This causes a secondary immune response which is faster (taking 1-3

What is the benefit to days), more specific (specific TH cells and Igs recruited) and uses antibodies
medicine and with higher affinity.
immunity because of
immunologic memory? It is said to be a result of antigen-specific lymphocytes that persisted for
years due to clonal expansion. This memory forms the basis for
vaccinations.
Describe the immune

response of naive B
Cells (primary
response).
Primary and Secondary Response of B Cells
In the primary response, antigen exposure and TH cell signals induce naive B cells
Describe the immune to become activated B cells then effector B cells called plasma cells.
response of memory B
Cells (secondary ● They secrete antibodies with low affinity and is limited to mainly IgM.
response). ● The response takes 5-10 days but Ig is continually secreted for months.
● Once the pathogen invasion is neutralized, the plasma cells undergo
apoptosis and antibody levels fall.
● Surviving activated B cells (not plasma cells) differentiate into memory B
cells.
In the secondary response, after exposure to the previously encountered antigen,

along with T cell help and cell differentiation, the memory B cells become plasma
cells used for a secondary immune response.
● These cells are faster (taking 1-3 days)

● Have a higher affinity due to somatic hypermutation and affinity maturation
● They use IgG, IgA, and IgE due to Ig class switching.
Primary response of B cells are generally longer and involves naive B cells with low affinity that use mainly IgM
antibodies. Secondary responses involved memory B cells that survive previous antigen encounters and have a
higher affinity, faster responses, and a repertoire of antibodies (IgA, IgE, IgG) based on the invading pathogen.
Primary and Secondary Responses of T Cells

In primary responses, antigen exposure and APCs induce naive T cells into
Describe the immune becoming activated T cells and eventually effector T cells (TH or CTL).
response of naive T
Cells (primary ● These T cells are slow, lacking specificity, based in the lymph nodes (due to
response). L-selectin) and respond in low frequencies.
● Activated T cells or Effector T cells can become memory T cells.
In secondary responses, upon exposure to previously encountered antigens, the

memory T cells become effector T cells (TH or CTL).
● Based in tissues (due to use of CAM which allows them to enter infected
tissues which places them at the front lines of infection).
Describe the immune
response of memory T ● They have more specificity (epigenetic changes causing faster transcription
Cells (secondary based on memory of the invading pathogen)
response). ● Respond faster and in a higher frequency (more specific T cells available for
response to due memory and proliferation due to epigenetic changes and
front line position).
Primary response of T Cells involves naive T cells which are slow and in low frequencies, lack specificity and are
limited to lymph nodes/lymphoid organs. Secondary responses involve memory T Cells which are based in tissues,
faster and in higher frequencies plus they are specific due to epigenetic changes.
How is homeostasis The body maintains homeostasis of lymphocytes through apoptosis where effector
maintained in cells and memory cells undergo cell death.
lymphocyte This does not cause immunodeficiency because the lymphoid organs and
populations? tissues can only hold a finite number of cells (a consistent population of
memory cells) that proliferate during an immune response but return to its
consistent amount (via apoptosis) after pathogen neutralization and the
signal molecules (cytokines, growth factors, ILs, costimulatory molecules)
fall.
Some memory cells and their daughter clones have adapted to the reduced
amount of signaling factors so they are more stable than other lymphocytes.
What is responsible for Apoptosis in cells is caused by the Fas-Fas ligand interactions where the trimeric
cell apoptosis? Fas receptor (FasL) on a lymphocyte or leukocyte binds to the Fas on a target cell
and triggers a biochemical pathway called the “Death pathway.”
● The Fas clusters and the biochemical cascade activates a proteolytic

Describe the process of enzyme called caspase which triggers other proteolytic enzymes in the
apoptosis. “Caspase Cascade.”
● It triggers the cytoplasmic enzyme, caspase activatable DNAase (CAD).
● CAD migrates to the nucleus of the cell and cleaves DNA into small
fragments which signifies the endpoint of apoptosis.
● Some gene promote apoptosis while others, like Bcl family genes inhibit
apoptosis.
○ The hypothesized high expression of Bcl in memory cells explain

why they are able to persist and resist antigen induced apoptosis.
Between the ages of 2-20, T and B cell maturity is still being developed but after
20, the rate of infection of an individual decreases until 60 where senescence
develops.
The body maintains homeostasis of lymphocyte populations via apoptosis where the Fas-FasL ligand interactions
occur which triggers the caspase cascade resulting in the caspase activatable DNAase migrating to the nucleus of
the target cell and cleaving DNA into small fragments. Some genes like Bcl genes are able to resist apoptosis. T and
B cells continue to mature until age 20 where the rate at which an individual gains infections is decreased. This rate
increases after age 60 due to immunologic senescence.
Chapter 20: Constitutive Defenses Including Complement
What are the Remember from Chapters 1-4, the Innate Immune System consists of barriers and
features of Innate nonspecific defenses (physical and molecular) to fight off invading pathogens. It interacts
Immunity? with the Adaptive Immune System via cytokines and inflammatory “danger” signals.
The specialized functions of the Innate Immune System are:

1. Rapid (within minutes-hours) nonspecific response to pathogens using Pattern
Recognition Receptors (PRR) to detect Pathogen-Associated Molecular Patterns
What are the (PAMP) (like lipopolysaccharides or mannan) on the surface of invading pathogens.
functions of Innate
Immunity? 2. Secretion of cytokines and inflammatory mediators to trigger the Adaptive Immune
System.
3. To detect changes in the body’s homeostasis due to the presence of invading

pathogens that signal infection or injury
This is a contrast to the functions of Adaptive Immunity:

1. Slow (within days-weeks) but specific response to pathogens using Antigen
Recognition Receptors to detect specific antigenic determinants (epitopes and
processed antigen peptides) from invading antigens.
How do the 2. It is triggered by the release of cytokines from the Innate System and the failure of
functions of Innate Innate immunity to stop an infection/invasion
Immunity differ from
the functions of 3. To detect the presence of nonself cells in the body or changes in self cells in the
Adaptive Immunity? body.
There are other morphological and evolutionary differences between the two.
● Innate Immunity is older and seen in all animals whereas adaptive immunity
evolved after innate immunity but only in vertebrates.
● Innate Immunity has no memory and relies on germlike genes to produce its
components whereas Adaptive Immunity uses memory and uses genetic
Describe variation/diversification to create its components.
evolutionary ● Very few pattern recognition molecules exist in Innate Immunity (<100) whereas
differences between Adaptive Immunity has exceeding amounts of antigen recognition molecules
Innate and Adaptive
(>millions)
Immunity.
● Innate Immune Cells do not malfunction whereas Adaptive Immune Cells can
malfunction leading to autoimmunity and Immune Complex Diseases
(Hypersensitivity).
Innate Immunity relies on physical and molecular barriers to prevent pathogen invasion as well as few pattern
recognition molecules to produce a rapid, nonspecific immune response against invading pathogens based on their
pathogen-associated molecular patterns and changes in homeostatsis. Innate Immunity is present in all animals, has
no memory, uses germlike genes and rarely malfunctions. In Contrast, adaptive immunity is only present in
vertebrates and relies on failure of Innate Immunity. It uses millions of antigen recognition molecules to produce a
slow but specific response and has memory and genetic variation/diversification but can cause autoimmunity.
What are the Barriers involved in Innate Immunity

specialized barriers of The specialized barriers of Innate Immunity are: Skin, Respiratory Tract and
innate immunity? Gastrointestinal Tract.
What role does the 1. Skin

skin play in innate
It is responsible for rapid responses to pathogen invasion and for
immunity?
informing/triggering Adaptive Immunity.
What are the main ● The epidermis is 90% keratinocytes, where dead keratinocytes make up the
epidermal cells in the outer layer (stratum corneum) and living keratinocytes make up the deep
skin? inner layer (epidermis).
What role do they play
in innate immunity? ● The dead keratinocytes are responsible for preventing pathogen penetration
into the deeper layers.
● The living keratinocytes are responsible for activating complement, and for
releasing interleukin-8 (IL-8) and tumor necrosis factor (TNF) upon damage
to their structure.
● Langerhans cells are responsible for presenting antigens to T Cells upon

migration to the local lymph nodes.
The skin is responsible for rapidly responding to invading pathogens and alerting adaptive immunity. Its main cells
are keratinocytes and Langerhans cells. The dead keratinocytes prevent pathogen entry into the deep layers/tissues
of the body and the living keratinocytes trigger the complement and release IL-8 and TNF. Langerhans cells
recognize antigens then migrate to lymph nodes to present them to T Cells.
2. Respiratory Tract
What role does the This refers to the upper (nose to bronchioles) and lower respiratory tracts
respiratory tract play (bronchioles to alveoli) which contain cells that secrete mucus and surfactant, a
in innate immunity? mixture of protein and phospholipids.
● Goblet cells in the upper respiratory airways are responsible for mucus
secretion which lines the airways to trap microorganisms.
What are the features
● The Cilia are responsive for “wafting” mucus toward the mouth and nose so
present in the
respiratory tract that the trapped microorganisms can be cleared via coughing or sneezing.
are involved in innate
● Mucosa responds to adaptive immunity where IL-17 from TH-17 cells (during
immunity?
Describe their extracellular pathogen response) stimulates the respiratory epithelium and
functions. IL-4 from TH-2 cells (during parasite/worm invasion and allergies) stimulates
hyperplasia, mucous secretion and smooth muscle hypertrophy.
● Type 2 pneumocytes on Alveolar Cells in the lower respiratory tract are

responsible for secreting surfactants which mainly prevent alveolar
collapsing but also contain pathogen-binding proteins from the collectin
family.
● The lower respiratory tract does not contain cilia and mucous as that would
disbenefit oxygen diffusion across the alveoli.
How do The respiratory tract relies on Igs, therefore patients with immunodeficiencies
immunodeficiencies experience frequent respiratory infections. Similarly, patients with cystic fibrosis have
and other diseases abnormal mucous secretion and patients with ciliary dyskinesia have defective cilia
impact the respiratory so they both experience respiratory tract infections.
tract?
The respiratory tract is responsible for secreting mucus and surfactants to eliminate microorganisms and prevent
microbial infections of respiratory organs. Mucous secreted by goblet cells are lined along the upper respiratory tract
by cilia and used to trap microorganisms which are then eliminated by coughing and sneezing. Surfactants secreted
by type 2 pneumocytes contain collectins which binds to pathogens. Patients with immunodeficiencies, abnormal
cilia or abnormal mucosal secretion experience frequent respiratory tract infections.
What are the Collectins Family:

collectins? They include Mannan Binding Lectin (MBL), Surfactant Protein A (SP-A), Surfactant
Protein D (SP-D), Collectin Liver 1 (CL-L1), Collectin Kidney 1 (CL-K) and Collectin
Live-Kidney Complex (CL-LK).
● They are structurally related to the complement protein C1q.
● The carbohydrate recognition domain is the globular head that recognizes

Describe the general
structure of collectins and binds to sugars on microorganisms so the microorganisms are
and their functions. opsonized.
● The alpha neck region joins the head to the collagen body.
● The collagen-like region provides structural stability.
● The N terminal segment of collagen-like domain is used for binding to other

cells like phagocytes.
○ They bind to specialized receptors on phagocytes and trigger
phagocytosis.
○ In the case of MBL, they trigger the complement
The collectins include MBL, SP-A, SP-D, CL-L1, CL-K1, CL-LK. They are structurally related to Cq1 and have a
globular head that binds to pathogens and triggers complement, collagen-like body for structure, alpha-helical neck
and N terminal segment for binding to phagocytes.
What role does the 3. Gastrointestinal Tract

gastrointestinal tract This includes the stomach, small intestine and colon which rely on gastric acid
play in innate (stomach) and bacteria (intestines) to defend against microbial infections.
immunity?
What feature of the ● The stomach contains gastric acid which has a pH low enough to kill
stomach is used as a pathogens (pH 1-2).
defense against ○ Likewise, patients with abnormal gastric acid secretion (difficulties in
microorganisms? secreting gastric acids) are at a higher risk of gastrointestinal
What do defects of infections, especially from food-borne microbes (in the case of
this feature cause? Salmonella).
What feature of the ● The lower gut contains exceeding amounts of harmless, commensal bacteria
gut is used as a that outcompete and kill harmful bacteria.
defense against
○ Epithelium in the gut secretes mucus but also transformation growth
microorganisms?
factor beta that induces Tregs to tolerate the harmless bacteria (so
How is this feature
protected? the body does not start an immune response against them).
Extracellular Molecules Involved in Innate Immunity

What are extracellular In addition to collectins, innate immunity uses interferons and proteins such as
molecules involved in complement and C-reactive proteins.
innate immunity?
Interferons
Interferons, a type of cytokine, get their name for their ability to interfere with viral
Why are these
replication and make cells mediated with interferons to be resistant to viral
cytokines called
infectious.
interferons?
They are categorized as Type 1 Interferons (IFN-α and IFN-β) and Type 2
Interferons (IFN-γ).
What are the types of ● Type 2 Interferons are mainly used for their immunostimulatory effects
interferons and their rather than their antiviral effects since they are better at triggering TH1 cells
main uses? ● Type 1 interferons are used for their potent antiviral effects.
The gastrointestinal tract uses the low pH of gastric acid in the stomach and the harmless bacteria in the gut to
prevent infections. Inefficiency in gastric acid increases the risk of infections. Harmless bacteria in the gut are
protected by tolerant Tregs. Innate immunity uses extracellular molecules like collectins, interferons, complement
and C-reactive proteins. Interferons are divided into Type 1 (IFN-α and IFN-β) used for antiviral effects and Type 2
(IFN-γ) used for immunostimulatory effects.
What cells secrete Type 1 Interferons:

Type 1 Interferons and ● They are secreted by plasmacytoid dendritic cells (an APC), macrophages,
during what conditions infected cells, epithelial cells and fibroblasts in response to infections and
does it occur? nonspecific injuries like trauma.
● During intracellular infections, viruses produce double-stranded RNA which

What is the PAMP and is a pathogen-associated molecular pattern that is recognized by the pattern
the PRR used during recognition receptor, toll-like receptor 3, on plasmacytoid dendritic cells.
intracellular viral
○ The plasmacytoid dendritic cells then secrete type 1 IFNs in
infections?
response.
● Using paracrine action (short-ranged cell signaling), type 1 IFNs inhibit viral
How are neighbouring
replication in neigbouring cells by degrading the viral genome and inhibiting
cells of an infected cell
protected from viral viral mRNA transcription. This prevents the virus from transmitting to other
infections? cells.
○ This is done through activating two intracellular enzyme pathways.
IFN activates an ● Type 1 IFN secretion activates NK cells to lyse infected cells.
innate cell and
improves the abilities ● Type 1 IFN also increases expression of MHC Class 1, improves antigen
of two adaptive cells. presentation of MHC Class 1 and improves the antiviral abilities of CD8+ T
What are these cells cells.
and how are they ○ This is done through their stimulation of transporter-associated
affected? antigen presentation (TAP), peptide transporters and proteasomes.
○ This also bridges innate and adaptive immunity by stimulating
How do IFNs bridge adaptive immune cells.
innate and adaptive
immunity?
Type 1 Interferons are secreted by plasmacytoid dendritic cells, macrophages, infected cells, fibroblasts and
epithelial cells in response to infection/injury, then theyuse paracrine action through activating 2 enzyme pathways to
inhibit viral replication in neighbouring cells. The dendritic cells use their toll-like receptor 3 to detect the mRNA of
viruses to trigger IFN secretion. IFN activates NK cells to lyse infected cells and it stimulates TAP, peptide
transporters and proteasomes to improve antigen presentation of MHC Class 1 molecules.
What is the use of ● Recombinant (genetically altered and recombined) Interferon-alpha is

recombinant used as a biologic/biopharmaceutical medical product in response to viral
interferon-alpha in hepatitis and some cancers like chronic lymphoid leukemia due to its
medicine? antiviral and immunostimulatory effects as well as is the ability to induce
apoptosis and malignant cell maturation.
How does this differ
It is administered via injection and is used in conjunction with antiviral
from antiviral
medication. However, it has side effects and can be neutralized by
infections?
antibodies.
What are the other Besides interferons, innate immune cells release other cytokines like IL-1, IL-6 and
cytokines released by TNF which activate adaptive immunity.
innate immune cells?
Complement
What are the basic The basic complement components range from C1 to C9 and are split into small
complement fragments (denoted by a common “a”) and large fragments upon activation.
components? Activation occurs through antibody-antigen interaction, which is why they are called
How are they
complement since they complement the abilities of the antibody which cannot kill
activated and why are
they named most pathogens on its own.
complement?
The complement cascade is triggered by three different pathways that activate the
How is the main complement, C3, which amplifies signals to activate three effector systems.
complement cascade
triggered?
Recombinant interferon-alpha is used as a biopharmaceutical product against viral hepatitis and cancers due to its
antiviral, immunostimulatory and apoptosis-inducing abilities, however, it can be neutralized by antibodies. Innate
Cells release other cytokines like IL-1, IL-6 and TNF which trigger adaptive immunity. The Complement system
consists of C1 to C9 and is activated by antibody-antigen interactions which causes it to break into large and small
(a) fragments. The cascade relies on 3 different pathways to trigger C3 and stimulate three effector systems.
What are three 1. Three Pathways to Activating the Complement (lectin, classical and
pathways used to alternative)
activate the
complement? I. Lectin Pathway
Describe the Lectin

Pathway.
● Mannose-binding lectin binds to the carbohydrates on the surface of

bacteria with its lectin head.
● Its Collagen-like domain activates C2 and C4 on the microbe’s cell surface
which induces the cleavage of hundreds of C3 which then forms C5
convertase.
The three pathways by which the complement cascade is activated are the lectin pathway, the classical pathway and
the alternative pathway.
In the lectin pathway, the lectin head of the mannose-binding lectin binds to carbohydrates on bacteria and its
collagen-like domain activates C2 and C4 on the bacteria surface to induce C3 cleavage and C5 formation.
II. Classical Pathway
Describe the Classical

Pathway
Classical Pathways activates C3 in molecules whose surface antigens are bound by

an antibody.
○ The first to be discovered but last to be evolved and it is based on
antigen-antibody complexes.
● When antigens bind to multiple antibodies, the total Fc portions of the Igs
trigger C1 if they are in sufficient amounts and at sufficient proximity.
○ This means that IgM is preferentially better at binding with C1 as it
has 5 Fc portions.
● After binding to the Fc, the C1, without the use of enzymes,
activates/cleaves C2 and C4 which then activates multiple C3 molecules.
In the classical pathway, C1 binds to the Fc portions of IgM or IgG sufficiently to cleave C2 and C4 to activate
multiple C3 molecules.
III. Alternative Pathway
Describe the
alternative
pathway.
The alternative pathway activates C3 on the surfaces of cells that lack membrane-bound surface
complement inhibitors.
● C3 is spontaneously activated on the cell surfaces due to constant low-level activation.
● On normal cells, membrane-bound surface complement inhibitors prevent spontaneous
activation of C3 but on pathogenic cell surfaces and self-cells with mutated inhibitors,
spontaneous activation of C3 occurs.
● Patients with these mutations experience hemolytic uremic syndrome, where uncontrolled
activation of C3 on platelets and epithelial cells leads to thrombosis.
● Similarly, uncontrolled cell death such as necrosis causes spontaneous activation of C3
(due to the cell contents leakage) which causes inflammation whereas programmed cell
death like apoptosis does not trigger C3.
In the alternative pathway, C3 is activated spontaneously on certain cell surfaces that lack inhibitors resulting in
thrombosis and hemolytic uremia syndrome. It is also triggered by necrosis (causing inflammation) but not
apoptosis.
Chapter 20
What are the results of C3 Amplification results from upstream, early components in the cascade triggering
C3 amplification? and cleaving downstream components into their effector molecules like fragments;
● Large (b) fragments that exhibit enzyme activity to cleave/activate or inhibit
downstream components and small (a) fragments that exhibit biological
activity to become anaphylatoxins.
What are
anaphylatoxins?
1. Anaphylatoxins
What is the result of These components are responsible for inflammation and immune cell recruitment.
C3 and C5 cleavage?
C3 and C5 cleavage produces C3a and C5:
C2a is cleaved to produce kinin. These cleavage products have a low molecular
which allows them to diffuse away from the site of complement activation and gives
How do them their specialized functions:
anaphylatoxins
perform immune cell ● Inflammation and Immune Cell Recruitment:
recruitment?
Anaphylatoxins act as signaling molecules that attract and activate immune cells like
leukocytes neutrophils, monocytes and macrophages to the site of complement
activation and increase their adhesion
How do they perform ● Cell Activation:

cell activation?
They bind to specific receptors on cells which trigger intracellular signaling pathways
that activate the cells
How do they aid in
vascular permeability? ● Vascular permeability:
The Kinin cause endothelial cells contract which increases vascular permeability.
How do they act as ● Chemotaxins:

chemotaxins?
They guide immune cells like leukocytes to the location where they are needed. The
leukocytes follow the diffusion gradient and once they reach the tissues,
anaphylatoxins then trigger phagocytosis and degranulation.
C3 amplification results in the amplification of signals which cleave components into small (anaphylatoxins) and
large (enzyme) fragments. Anaphylatoxins (C3a, C5a and kinin) are components created from C3 and C5 cleavage
and can recruit immune cells and increase their adhesion, trigger intracellular pathways to activate cells, increase
vascular permeability and guide immune ells to inflamed sites to trigger phagocytosis and degranulation.
Chapter 20
What is the membrane Membrane Attack Complex (MAC)

attack complex? This is the final part of the complement cascade and it is responsible for eliminating
pathogens and inducing lysis in target cells (particularly bacteria like Neisseria).
● C3 activates the downstream components to recruit C5 to C9 for MAC

How does the
formation.
membrane attack
● The enzyme activity of C5 (particularly C5b) and C6 allows C7, C8 and
complex form?
multiple C9 to insert themselves in the plasma of target cells.
● C6, C7 and C8 bind to C5b on the target surface to create a platform for C9
polymerization.
● 10 to 16 C9 polymerizes (joins together) and penetrates the target cell to
enter the lipid bilayer of the cell.
● The polymerized C9 molecules form a pore (transmembrane channel) which
allows an influx of ions and water to enter the cell, swell the cell then rupture
it (lysis).
Complement Receptors (CRs)

What are complement
receptors? These are receptors present on cells that bind to early components like MBL, C1
and activated C3 & C4.
Opsonization:
How do CRs act as ● C3 acts as an opsonin, meaning it marks pathogens for phagocytosis by
opsonins? binding the pathogens to phagocytes.
● The abundance of C3 produced during component activation and the fact
that C3 can bind to 3 different receptors on various phagocytes makes it a
good opsonin.
● IgG can also serve as an opsonin when it binds to Fc receptors on
phagocytes, however, IgM cannot since phagocytes do not possess Fc
receptors for IgM. Therefore C3 must be used during an IgM-dominated
immune response (like the primary response).
The membrane attack complex is a pore formed from polymerized C9 molecules as a result of C5 &C6 enzyme
activity which allows ions and water to enter and swell the cell. Complement receptors bind to the early components
in which C3 (as well as IgG) can act as opsonin by binding to and marking phagocytes for phagocytosis.
Chapter 20
B Cell Stimulation:
● C3 binds to CR2 receptor on B cells to provide costimulation which reduces the
threshold needed for B cell activation and promotes antibody production
How do CRs aid in B (especially in the classical pathway when complement binds to antigens then
Cell stimulation? binds to CR2).
● CR2 is subverted by Epstein-Barr Virus since the virus uses CR2 to gain entry
into the cell.
Immune Complex Clearance:

What complications The insoluble lattices of antigen-antibody complexes are immune complexes and are
arise from uncleared found in blood and tissues. If they are not cleared, they cause chronic inflammation and
immune complexes? immune complex diseases.
● Such is the case in patients with immunodeficiencies like complement
In what circumstance
deficiencies.
do immune complex
● High amounts of C3 can interrupt the lattices of large insoluble complexes that
diseases cause?
are hard to clear, thus, making them soluble.
● C4 and C3 in soluble immune complexes bound to CR1 receptor on red blood
How do CRs aid in the cells which allows the complexes to be transported to organs abundant in
clearance of immune phagocytes (liver, spleen)
complexes? ● The phagocytes use their own complement and Fc receptor to phagocytose the
complexes without harming the RBCs.
Complement Inhibitors
What role do Excessive complement activation leads to inflammation and widespread cell lysis.
complement inhibitors Therefore inhibitors are necessary at every stage of the complement cascade such as:
play? ● Early inhibitors: C1 inhibitor prevents C1 activating C4 and C2
● C3 inhibitors: Membrane-bound surface inhibitors prevent C3 activation
What are the inhibitors ● MAC inhibitors: Membrane-bound surface inhibitors also prevent MAC
and their functions? formation.
Complement Deficiencies and Defects

● Defects in inhibitors lead to atypical hemolytic uremic syndrome and hereditary
angioedema.
What are the possible ● Complement deficiencies lead to immune complex diseases like systemic
complement
lupus erythematosus
deficiencies and what
● Deficiencies in downstream components, especially C9, lead to recurring
are the consequent
bacterial infections.
effects?
CR2 provides a platform for C3 to bind to which provides costimulation so less stimulation is required to activate B
cells and antibody production but some viruses like EBV can use CR2 to gain entry into cells. Uncleared
antigen-antibody (immune) complexes can lead to immune complex diseases, especially in the case of complement
deficiency. C4 and C3 binding to CR1 allows it to be transported to phagocyte-rich areas for phagocytosis.
Complement Inhibitors (early, C3 and MAC) prevent spontaneous/excessive complement activation by inhibiting
components. Complement deficiencies like inhibitors, complement and downstream deficiencies lead to diseases
like hereditary angioedema, systemic lupus erythematosus and bacterial infections.
Chapter 21: Phagocytes
What is Phagocytosis is the process by which phagocytes internalize particulate matter into
phagocytosis? cytoplasmic vesicles upon recognition of a pathogen.
Phagocytosis is achieved by:

● Lysosomes which are granules containing enzymes that fuse with cytoplasmic
How is phagocytosis
achieved? vesicles and degrade material inside of it
● Phagocytic enzymes lead to toxic molecules production which causes oxidative
burst in phagocytized organisms.
As a result of phagocytosis, phagocytes are needed to:

What role do ● Phagocytize and remove small extracellular pathogens (bacteria, fungi, protozoa
phagocytes play in
and cellular debris)
innate immunity?
● To alert the adaptive immune system to the presence of infections using cytokines
and cell-surface molecules.
Types of Phagocytes
What are the types of Phagocytes are bone marrow-derived (myeloid) cells and are mainly into two types:
phagocytes? neutrophils and macrophages (and macrophage subtypes).
1. Neutrophils
What are neutrophils They are multinucleated phagocytes containing granules of proteolytic enzymes.
and what are their ● They are a part of the early defense against bacterial infections but only enter
main function in tissues when they are infected/inflamed. Otherwise, they circulate the blood.
immunity?
● During infections, they migrate to the site of infection to kill pathogens. After
How do they respond
to pathogen destroying pathogens, they die and form pus (which is largely composed of dead
invasions? neutrophils).
What implication do ● Defective neutrophils or neutropenia (low levels of neutrophils) increases the risk of
they cause in low serious bacterial infections in patients.
levels? ○ Neutropenia can be caused by cytotoxic drugs.
● They are quantifiable during the acute-phase response by automated instruments.
Describe their life ● They are produced daily but only survive a few hours to maintain homeostasis.
span and population However, during infections, their numbers increase due to increased production.
during and outside of
an infection. ● Despite their short life, neutrophils make up the majority of the phagocyte
population.
Phagocytosis is the process by which phagocytes (neutrophils and macrophages), after recognizing a pathogen,
internalize the pathogen and use lysosomes and enzymes to kill the pathogen. This is necessary to remove small
extracellular pathogens and alert the adaptive immune system of an invasion. Neutrophils are short-lived, circulating
mutinucleated phagocytes that enter inflamed tissues. They increase in production during infections but once they
kill pathogens, they die and form pus.
Macrophages:
What are These are large, irregularly shaped, specialized phagocytes containing cytoplasmic
macrophages? granules and vacuoles able to migrate into tissue without the presence of
inflammation.
They include:
Monocytes
● They are immature macrophages derived from myeloid cells and located in
What are monocytes?
the blood.
● Then they migrate to tissues to become mature, specialized macrophages.
Tissue Macrophages
What are tissue ● These are large cells with specialized granules and cytoplasmic
macrophages? compartments.
Describe their ● Histocytes are active tissue macrophages found in bone marrow and lymph
functions. nodes.
● They can also clear dead macrophages.
Giant and Epithelioid Cells

● Macrophages undergo further maturation to become multinucleated giant
What are the giant and
cells or epithelioid cells in the presence of chronic inflammation.
epitheloid cells?
● The maturation is mediated by T Cell cytokines and the mature cells are
What are their characteristic of granuloma formation.
functions? ● They do not form pus and they live for years, unlike neutrophils.
● Giant and epithelioid cells are responsible for prolonging the inflammatory
How do they differ response by presenting antigens to T cells and by secreting cytokines.
from neutrophils?
Macrophages are irregular phagocytes containing cytoplasmic granules and vacuoles. They can be found in various
forms: Monocytes-immature macrophages that become mature/specialized in tissues, tissue macrophages- large
cells that clear dead macrophages and contain specialized granules, histocytes- tissue macrophages in bone
marrow and lymph nodes and giant-epithelioid cells -mature, specialized macrophages that form granuloma in the
presence of chronic inflammation.
What are fixed Fixed Macrophages

macrophages and ● These are specialized phagocytes that line sinusoids in the spleen and liver
how do they (Kuppfer cells).
function? ● They phagocytize circulating particular matter (and sometimes large cells).
What are alveolar Alveolar Macrophages

macrophages and ● These are macrophages lining the alveoli and are involved in the innate defenses
how do they of the lungs.
function? ● They are involved in diseases like chronic obstructive pulmonary disease (COPD).
Gilial Cells
What are gilial cells
● They are long-lived macrophages within the nervous system and are responsible
and how do they
for clearing dead neural cells.
function?
Osteoclasts
What are
● These are very specialized macrophages found in bone and participate in calcium
osteoclasts and
how do they metabolism by resorbing bone and releasing calcium into the blood.
function?
Generally speaking, Neutrophils have highly variable production and blood levels which
both increase during infections.
● Their life cycle is short as they die after migrating into inflamed tissues and
combating pathogens (using phagocytosis, NET, toxic molecules/enzymes).
● They have a single mature form and use short-lived secretion of chemokines to
Describe the recruit neutrophils. They also respond to IL-17 from the adaptive immune system
differences in the but do not provide signals for adaptive immunity.
key features of
Neutrophils and Comparatively, Macrophages are steady in production and blood levels and can migrate
Macrophages? into tissues that are not inflamed.
● They have multiple mature forms dependent on the tissue they migrate into and
they survive even after encountering and killing pathogens (using phagocytosis and
toxic molecules/enzymes).
● Macrophages secrete IL-8, TNF and IL-1 to recruit neutrophils and respond to
IFN-γ from adaptive immunity. Likewise, it secretes IL-12 and TNF to stimulate the
adaptive immune system as well as by presenting processed antigens and
providing costimulation.
Fixed Macrophages line sinusoids and phagocytize particular matter, alveolar macrophages line the alveoli and
defend against lung infections, gilial cells remove dead neural cells from the nervous system and osteoclasts are
macrophages found in bones for calcium metabolism. Neutrophils are short-lived, pyogenic, respond to IL-17 and
have one single mature form whereas macrophages last longer, have multiple mature forms, secretes IL-8, TNF, IL-1
and respond to IL-12 and TNF.
How are phagocytes Phagocyte Production

produced? ● Neutrophils and monocytes are produced from the same stem cells but more
neutrophils are produced than monocytes.
What mediates ● Colony-stimulating factors (CSFs) produced by tissue macrophages during
phagocyte the acute-phase response is responsible for the phagocyte production,
production?
especially during infections.
○ In the case of neutropenia or stem cell transplants, recombinant
CSFs are used to stimulate phagocyte production.
Phagocyte Recruitment
Monocytes constantly migrate into healthy tissue and differentiate into macrophages
How do monocytes which remain inactive unless they are stimulated by signals (receptors).
recruit neutrophils?
Resident macrophages at inflamed sites release cytokines and chemokines, TH-17
secretes IL-17 which stimulates:
● Neutrophil production
● Neutrophil and endothelium expression of selectins and integrins
● Neutrophil adherence to endothelium in local vessels (diapedesis)
● Chemotaxis to infection sites
Chemokines
What are Chemokines are low-molecular-weight chemotactic cytokines that direct cells to
chemokines? specific sites of infection or inflammation.
● THelper 17 cells (TH-17) secrete IL-17 which recruits neutrophils to the
inflammed sites. Likewise, local macrophages secrete chemokines and other
What are the various cytokines to recruit neutrophil.
chemokines involved
in cell recruitment? ● Anaphylatoxins also act as chemotactic for phagocytes.
○ Example: Local macrophages secrete cytokines which stimulates
endothelial cells in local capillaries to increase P-selectin and
integrins like intracellular adhesion molecules (ICAMs).
● P-selectin and integrins are adhesion receptors/molecules
● These attract neutrophils to the site. Similar to how cell signaling attracts
lymphocytes.
Neutrophils and macrophages are produced from the same stem cells under the mediation of colony stimulating
factors. Monocytes secrete IL-17 which stimulates neutrophil production, receptor expression, diapedesis and
chemotaxis to infected sites. Chemokines, like IL-17 from TH17 cells, anaphylatoxins and adhesion receptors
(P-selectin and integrins) are the signalling cytokines responsible for recruiting neutrophils and other immune cells to
infected sites.
What processes do Chemokine secretions mediate diapedesis and chemotaxis:

chemokines mediate? Diapedesis
● This is the process by which cells squeeze through cell walls to enter
What is diapedesis tissues.
and how is it affected ● Macrophages at the sites of infections secrete chemokines like IL-8, which
by chemokines?
modifies neutrophil integrins make them adherent which allows easier
binding to the epithelium to facilitate diapedesis.
Chemotaxis
What is chemotaxis ● This is the directional migration of cells along a gradient of chemokines.
and how is it affected ● This attracts neutrophils to the inflamed tissues but also signal local dendritic
by chemokines? cells for lymph nodes to trigger adaptive immunity.
Receptors on Phagocytes
Phagocytes use a variety of receptors:
What are the kinds of
receptors used by
● Cytokine and Chemokine Receptors: Necessary to direct phagocytes to
phagocytes?
inflammation sites and prepare them to phagocytize pathogens.
● Pattern Recognition Receptors: At least two different receptors are needed
to detect pathogen and damage-associated molecular patterns
Receptors Involved:
What are TLRs? Toll-Like Receptors (TLRs)

These consist of 10 different membrane molecules and are found on macrophages,
APCs (B cells, dendritic cells), and epithelial cells.
They are:
● TLR2
What is the function of
Recognizes the ligands: sugar and lipoproteins associated with bacteria. It is
TLR2?
widespread on all cells.
WHat is the function of ● TLR3

TLR3? Recognizes the ligands: Double-stranded RNA associated with viruses. It is
expressed on dendritic cells and epithelial cells.
Chemokine mediates diapedesis (cells squeezing into cell walls) and chemotaxis (directional migration of cells
along a chemokine gradient). Phagocytes use chemokine/cytokine receptors for chemotaxis to inflamed sites and
pattern recognition receptors to detect pattern/damage associated patterns. Toll-like receptors are PRRs found on
macrophages, APCs, epithelial cells. TLR2 on all cells and recognizes sugar and lipoproteins of bacteria whereas
TLR3 on dendritic cells and epithelial cells recognizes double-stranded RNA of viruses
What is the function of ● TLR4

TLR4? Recognizes the ligands: lipopolysaccharides (LPS) associated with gram-negative
bacteria and forms a complex with CD14. It is expressed on macrophages.
● TLR5
What is the function of
Recognizes the ligands: flagellae associated with motile bacteria. It is expressed on
TLR5?
macrophages.
● TLR7
What is the function of Recognizes the ligands: Single stranded RNA associated with viruses. It is
TLR7? expressed on dendritic cells and macrophages.
● TLR9
What is the function of Recognizes the ligands: Unmethylated cytosine and guanine sequences (CpG)
TLR9? associated with bacteria. It is expressed on dendritic cells and B cells.
● TLRs are necessary to recognize infections but their roles overlap so several
What are some TLRs are triggered by any infection.
characteristics of ● When bound to pathogens, they initiate intracellular signals that causes
TLRs? cytokine production. They can also be used as targets for drugs due to their
potent effects.
C-Lectin Receptors
Lectins are proteins that recognize the carbohydrates on pathogen surfaces and
What are C-Lectin C-Lectin receptors recognize the lectins bound to the pathogens.
Receptors? This is not MBL, MBL is a lectin that recognizes mannose.
The C-lectin receptors recognize the sugars as:

What do CLRs ● Sequences/patterns on glycolipids, glycoproteins on pathogen cell surfaces
recognize? or dying mammalian cells.
Bound C-lectin receptors activate macrophages leading to cytokine production.

● They can also capture and bind to pathogens then deliver them to endocytic
What are the functions production.
of bound CLRs? ● APCs like macrophages and dendritic cells need C-lectin receptors are
required to degrade pathogens and T Cell presentation.
TLR4 on macrophages detect lipopolysaccharides on gram-negative bacteria and complexes with CD4. TLR5 on
macrophages recognizes flagellae on motile bacteria. TLR7 on dendritic cells and macrophages detect
single-stranded RNA in viruses. C-lectin receptors lectin bound to pathogens to detect PAMP like gycolipids and
glycoproteins
What do complement Complement Component Receptors

allow phagocytes to Phagocytes binding to complement allows them to bind to:
bind to? ● Binding to pathogens opsonized by complement
● Immune Complexes of antigen-antibody-complement
● Dead Cells
Immunoglobulin Receptors
How do the Ig
● IgG can act as an opsonin when they are bound to an antigen on their
receptors impact
phagocytes? antigen-binding site and are bound by the Fc receptors of Phagocytes. IgG
triggers phagocytosis through the phagocytes Fc Receptor.
Actions of Phagocytes
What are the actions Macrophages and Neutrophils both use phagocytosis and the release of toxic
of phagocytes? molecules and enzymes.
However:
● Macrophages, due to their long life, play a role in communication between
innate and adaptive system
● Neutrophils, due to their short lives, cannot do much besides killing and they
use neutrophil extracellular traps (NETs)
What is phagocytosis? 1. Phagocytosis

● It is triggered by pathogens binding to one of the phagocyte receptors, but
most effectively by pathogens opsonized by complement or IgG
● When pathogens are ingested, phagosomes are formed.
When phagocytes bind to complement, it gives them the ability to bind to complement-opsonized pathogens,
immune complexes with complement and to dead cells.IgG bound to an antigen while bound to a phagocyte by their
Fc receptor opsonizes the pathogen and triggers phagocytosis. Phagocytes use phagocytosis and toxic
molecules/enzymes, however, macrophages are involved in communication between adaptive & innate immunity
while neutrophils deploy neutrophil extracellular traps to kill phagocytes. Phagocytosis is triggered when pathogens
are opsonized by IgG or complement or when they are bound by phagocytes. Upon ingestion, phagosomes are
formed.
What is oxidative 2. Oxidative Burst

burst? Once pathogens are phagocytosed, three interrelated enzyme pathways are
activated to produce toxic molecules that further damage pathogens.
The toxic molecules are:

What are the toxic
molecules used in ● Hydrogen peroxide (phagocyte nicotinamide adenine dinucleotide phosphate
this? [NADPH] oxidase),
● Hypochlorous acid (bleach [myeloperoxidase]),
● Nitric oxide (inducible nitric oxide synthetase [macrophages but not
neutrophils]).
Describe the effects of Nitric oxide not only is toxic to pathogens but it can also serve as a neurotransmitter
nitric oxide. and in maintaining vascular tone when secreted by neuronal and endothelial cells in
low levels.
How does Nitric oxide also reduces vascular tone and cardiac output and it contributes to low
immunodeficiency blood levels (in septic shock) when it is produced in high levels by macrophages
affect nitric oxidase? (due to inducible nitric oxide synthetase being activated).
● In the case of primary immunodeficiency called chronic granulomatous
disease, the phagocyte NADPH oxidase enzymes are defective.
3. Proteolytic Enzymes
What are proteolytic
enzymes? ● The main enzymes are proteolytic and can digest bacteria in the acid pH of
the lysosomes.
○ Should the enzymes leak out of phagocytes, serpins such as
α1-antitrypsin prevent tissue damage.
Where are the ● In macrophages, the proteolytic enzymes are contained in lysosomes which
enzymes located in can be regenerated during the macrophages' long life.
macrophages and ○ The digested peptides can be presented to T cells.
neutrophils? ● In neutrophils, the proteolytic enzymes are contained in granules but the
neutrophils die once the granules are used up.
Oxidative burst employs three enzyme pathways to produce toxic molecules: hydrogen peroxide, hypochlorous acid
and nitric oxide, to damage pathogens. Nitric oxide also has modulatory effects of maintaining vascular tones and
reducing cardiac output. Phagocytes also use enzymes that are proteolytic that digest bacteria, and are found in
macrophages’ lysosomes and neutrophils’ granules. If enzyme leakage occurs, serpins prevent tissue damage.
What other Besides enzymes, other substances also leak into phagosomes:
substances are used ● Defensins: low molecular weight peptides that punch holes into bacteria.
by phagocytes? ● Lactoferrins: bind to iron in bacteria to deprive them of those nutrients.
● NETs: (Only done by neutrophils), are used when pathogens are too large or
too numerous.
NETs: When neutrophils are activated, they break down their own cell membrane and
extrude chromatin (a mixture of DNA and histones).
Describe the ● The chromatin unravels to produce a trap that physically captures pathogens
neutrophil and destroys them (while restricting the toxic enzymes and proteolytic
extracellular trap. enzymes).
● This may be risky since the exposed DNA can be detected as an antigen and
contribute to autoimmune disease systemic lupus erythematosus.
Inflammatory Signalling
Prostaglandins and leukotrienes are inflammatory mediators produced by phagocytes.
● Neutrophils are still too short-lived to produce a long-lasting inflammatory
What are the
inflammatory response so they have a short-lived, pyogenic (pus forming) inflammatory
mediators used by response instead (besides the release of nitric oxide and chemokines).
phagocytes? ● Macrophages have a chronic (long-lasting) inflammatory response by
secreting soluble messengers with local and systemic effects.
● Macrophages also serve as APCs since they process antigens, secrete
How are their cytokines, and express high levels of MHC Class 2 and costimulatory
inflammatory molecules.
responses affected ○ If the antigen isn't cleared, chronic inflammation and granuloma
by this? formulation is the response.
Phagocytes also use defensins, lactins and NETs (neutrophil-only) to puncture bacteria and deprive them of
nutrients. NETs are traps revealed by chromatin which captures pathogens and destroys them but risks
autoimmunity in the process. Phagocytes use inflammatory mediators like prostaglandins and leukotrienes to create
an inflammatory response: neutrophils have a short-lived pyogenic response whereas macrophages have a chronic
inflammatory response. They also serve as APCs due to their antigen processing and cytokine secretion and
MHC/costimulatory molecule expression.
Describe the process Acute Phase Response

of the acute phase
response. ● After the PRRs on macrophages recognize a pathogen, the macrophages
secrete cytokines: IL-7, IL-6 and TNF which increase complement and arm
the adaptive immune system.
● These cytokines also affect the central nervous system (CNS) through
receptors in the hypothalamus resulting in an increase in body temperature
during infections (intended to inhibit viral and bacterial replication).
○ The cytokines also encourage increased metabolic rate and anorexia
which is why there is weight loss during serious infections.
● Macrophages also secrete IL-8 (a chemoattractant) which attracts
neutrophils to the site of infection.
● Dendritic cells can secrete IL-12 when stimulated through their TLR which
activates nearby T cells and alerts the adaptive immune system.
What are phagocyte Phagocyte Defects

defects? Primary disorders of phagocytes are rare and result in diseases such as chronic
granulomatous.
● Secondary disorders are common, the most important being neutropenia

where the neutrophil population is reduced (due to some drug treatment).
Describe the causes
of some phagocyte ● Phagocyte dysfunctions may also be caused as a consequence of other
defects diseases such as diabetes, renal failure and corticosteroid drug treatments.
● Corticosteroids are used for treating inflammation, however, they also
suppress immunity against infections and cause metabolic problems and
hypertension.
○ At low doses, they impair phagocytes and at high doses they impair
lymphocytes
The acute phase response is triggered when PRR on macrophages recognizes PAMP/DAMP and secretes IL-7, IL-6
and TNF in response. The cytokines increase complement, alert adaptive immunity and raise the body’s
temperature through the CNS. IL-8 is also secreted to attract neutrophils and IL-12 is secreted by dendritic cells to
activate nearby T Cells. If phagocytes are dysfunctional (due to some diseases or drugs), primary diseases can
occur causing granulomatous or secondary diseases can occur causing neutropenia. Corticosteroids especially can
impair phagocytes at low doses and lymphocytes at high doses.
Comparison of Innate and Adaptive Molecular Mechanisms
What are the Abilities of Adaptive Immunity:

specificities of ● Antigen recognition molecules such as TCRs, Igs and MHC molecules are
adaptive immunity? used to recognize millions of antigens.
● It can also distinguish between self, nonself and self that are
damaged/infected.
What are its Incapabilities of Adaptive Immunity:

drawbacks? ● They can't tell when the body is in homeostasis or in danger (without the
help of innate immunity danger signals) therefore it cannot respond
autonomously without reacting to self-peptides and causing autoimmunity.
Abilities of Innate Immunity:

What are the abilities ● Pattern recognition receptors like TLRs on phagocytes like macrophages
of innate immunity? can recognize pathogen-associated molecular patterns or
damage-associated molecular patterns.
● It can distinguish danger, tissue damage and infections
● The activated innate cells secrete cytokines and express increased amounts
of MHC 2 molecules and costimulatory molecules like CD80
● The cytokines and costimulatory molecules expression is called a danger
signal, which is needed to trigger adaptive immunity.
What is its Incapabilities of Innate Immunity

drawbacks? ● It is nonspecific and cannot differentiate between self and nonself.
Innate immunity uses PRRs like TLRs on macrophages to detect PAMPs and DAMPs in order to distinguish
between homeostasis and danger, tissue damage or infection. It uses cytokines and costimulatory molecules to
create a danger signal to alert adaptive immunity. It cannot differentiate between self and nonself. Adaptive immunity
uses antigen recognition molecules like Igs, TCRs and MHC to distinguish between self, nonself and altered self
cells. It cannot, however, tell the difference between homeostasis and danger, so they rely on innate immunity for
danger signals.
How do cytokines Connection between Innate and Adaptive Immunity

connect innate and ● Danger signals connect both immunities as innate's danger signals are
adaptive immunity? needed to trigger adaptive T cells and to help in peripheral tolerance to
prevent autoimmunity and allergy/hypersensitivity of adaptive immunity.
● The Fc receptors of macrophages respond best to pathogens opsonized by

IgG and TH1 cells are required to stimulate IgG production.
● Macrophages rely on (IFN-γ) secreted by TH1 cells for support and

maintenance during chronic infections.
The human immune system relies on both forms of immunity, and deficiencies in any
Which form of
part (immunodeficiencies) impair the entire body's defense. There is no better form
immunity is better?
of immunity between the two as neither can properly function without the other.
Danger signals from innate immunity connects innate and adaptive immunity. Innate cells, lime macrophages, have
receptors which rely on pathogens opsonized by adaptive immunity and cytokine secretion from adaptive cells. Both
forms of immunity are interconnected and the human body relies on both. Therefore, neither is great than the other.
Chapter 22: Killing in the Immune System
How do phagocytes The innate cells, mast cells and natural killers, are responsible for destroying the
and innate cells deal pathogens: parasitic worms and viruses (virally infected cells) respectively using apoptosis.
with infections?
Features of Parasitic Worms:
● Variety in shapes and sizes (1mm to 10m)
● Has a complicated life cycle of eggs larvae and adult forms.
● The eggs are not affected by the stomach's low pH (an innate barrier) and cannot
What are some be broken down by proteolytic digestion in the stomach.
features of parasitic ● They only hatch in the lower gut so the adult worms live inside the lower gut and
worms? are protected from immune responses.
Because of these features, innate cells (mast cells and eosinophils) are evolved to remove
the parasitic worms by:
● Discharging toxic substances into the gut lumen
● Increasing mucus secretion
● Increasing smooth muscle contraction
○ (This evolutionary adaption is also seen in airways)
How do innate cells
deal with worm
infections?
What are some

features of mast
cells?
Mast Cells
● They are derived from unknown precursor cells in the bone marrow under the
influence of IL-3 and IL-4 from TH2 cells.
● They enter tissues like connective tissues, mucosa and skin (especially during
worm infections).
What receptors do
mast cells use?
Mast cells in tissues produce granules containing mediators and bind to IgE on their Fc
receptors FcεRI (with high affinity).
● Mast cell FcεRIs are specialized, as they do not bind Ig already bound to antigen
and they cause mast cell activation only when the surface IgE are crosslinked by
antigen.
Innate cells use apoptosis to destroy invading pathogens, worms and virally infected cells. Parasitic worms are very
variable and are able to survive the stomach and intestines, the latter in which they live. To combat this, innate cells
discharge toxic substances, stimulate mucus secretion and increase smooth muscle contraction to remove
parasites. Mast cells are formed under IL-3 and IL-4 from TH2 cells and enter tissues during worm infections. They
use their Fc receptor ( FcεRI) to bind to unbound IgE and is activated by crosslinked antigens.
How are mast cells Mast cells are also activated by anaphylatoxins C3a and C5a and by several drugs.
activated and what ● Mast cell activation results in; degranulation (preformed substances are
is the result? released from granules) and Arachidonic acid metabolism (produces a
range of freshly made mediators)
What are the mast

cell enzymes?
How do they
function?
Granule Contents in Mast Cells:

Mast Cell Enzymes
These are proteolytic enzymes like tryptase and chymotrypsin.
What is histamine? ● These are responsible for increased mucus secretion and smooth muscle
contractions (in bronchi and gut).
● They cleave and activate complement components and kinin pathways which
leads to inflammation.
How does it ● The levels of enzyme tryptase in the blood can be used in the diagnosis of
function? serious allergic reactions.
Histamine
It is responsible for smooth muscle contraction in the gut and lungs in order to expel
worms.
● It also increases vascular permeability by causing endothelial cell contractions
What is the purpose which leads to a widening of intracellular gaps and tissue edema.
of mast cells ● It serves as a chemotactic signaling molecule to attract white cells to the
secreting cytokines? infected sites. It also causes itching at the infected sites.
Cytokines
Mast cells produce cytokines to promote and extend the inflammatory phase.
● Preformed TNF in the granules activates local endothelium to enhance the
diapedesis of inflammatory cells.
● Activated/stimulated mast cells IL-4 to stimulate TH2 responses, IL-3 and IL-5
stimulate eosinophil production and activation and IL-4 and IL-5 move adaptive
immune responses from TH1 response.
Mast cells are activated by anaphylatoxins (from the complement system) and in response, undergoes
degranulation, and arachidonic acid metabolism. Mast cells contain granules which are proteolytic enzymes
(tryptase, chrymotrypsin), histamine and cytokines to expel worms from the gut and promote inflammation.
What triggers Arachidonic Acid Metabolites

arachidonic acid Mast cell exposure to antigens can activate arachidonic acid metabolism.
metabolism? (Phagocytes can also produce it).
It occurs in 2 pathways:
Describe the
● The cyclooxygenase pathway which produces prostaglandins:
cyclooxygenase
The prostaglandins stimulate vasodilation (within seconds), increase vascular
pathway.
permeability, constrict smooth muscle in the gut and bronchi and can inhibit TH1
cells.
Describe the ● The Lipooxygenase which produces leukotrienes:
lipooxygenase Leukotrienes have slower effects than prostaglandins. They contribute to the smooth
pathway muscle contractions, function as a chemotactic stimulus for neutrophils and
eosinophils, and is responsible for converting responses to either delayed or chronic
(cellularity of immediate response)
Immediate Response:
What is the immediate
Mast cells are located at frontline tissues of parasitic infections and are able to
response?
respond quickly to antigen stimulation.
What is it triggered ● The immediate response is caused by Histamines, Prostaglandins and

by? Proteolytic enzymes
What does it cause? ● And it results in Smooth muscle contraction, Increased vascular permeability
and Mucus secretion
The late response is caused by Cytokines and Leukotrienes

What causes a late ● And results in Influx of eosinophils, Influx of TH2 cells and Possible chronic
response and what
inflammation (not granulomata -macrophages and TH1 cells).
does it result in?
Eosinophils
What are eosinophils? They are like mast cells except they are recruited to tissues during certain types of
Name some features inflammation and they have granules with particular toxic substances.
of them. ● They are recruited to parasite-infested sites by chemokine eotaxin and
leukotrienes produced by epithelial cells and mast cells respectively
● They are present in blood but only in small numbers.
Arachidonic acid metabolism is triggered by mast cell exposure to antigens. The 2 pathways are cylooxygenase
pathways (prostaglandins causing vasodilation, smooth muscle constriction and inhibiting TH1 cell) and
lipooxygenase (leukotrienes causing chemotactic stimulus neutrophils and eosinophils, and delayed or chronic
infections). Mast cells, histamines, prostaglandins and proteolytic enzymes immediate responses (vasularity, muscle
contraction and mucus secretion) whereas cytokines and leukotrienes cause late response (influx of eosinophils,
TH2 cells and chronic inflammation).
What are Eosinophils

eosinophils ● They are derived from precursors similar to neutrophils under the influence of
activated by and IL-3 and IL-5.
what mediates ● IL-3 and IL-5 secreted from TH1 and mast cells also increased eosinophil
their production? production (eosinophilia is the increased presence of eosinophils in the blood).
● They are activated by cytokines, chemokines, and cross-linked IgE on FcεRI.
What is the result

of eosinophil
activation?
Upon activation, eosinophils release the same mediators as mast cells with the
What is immediate exception of histamine and 3 specialized mediators:
hypersensitivity? ● Peroxidase which generates hypochlorous acid upon contact with parasites
● Major basic proteins that damage parasites' outer surfaces and host tissues.
● Cationic proteins (neurotoxin) that damage the outer surface and the simple
nervous system of the parasite.
What causes
immediate
hypersensitivity? Immediate Hypersensitivity (Type 1 Hypersensitivity)
The immediate responses of mast cells and eosinophils degranulation lead to
immediate hypersensitivity (even though mediators can cause a delayed, chronic
response).
Some of these mediators are targets for allergy treatment.
What are Natural The hypersensitivity is as a result of eosinophils and mast cell responding to innocuous
Killers? antigens like pollen since parasitic worms are not a threat in the developed world.
Natural Killers
These cells are responsible for killing virally infected cells and for stimulating the
adaptive immune response.
● The name natural is due to the ability to interact with target cells without priming
(likewise, natural antibodies and natural T reg cells).
Eosinophils develop by IL-3 and IL-5 from TH1 and are activated by cytokines, chemokines and cross-linked IgE on
FcεRI. It releases the same mediators as mast cells but also peroxidase, major basic proteins and cationic
proteins that all damage parasites. Mast cells and eosinophils degranulation can cause immediate
hypersensitivity in response to innocuous antigens (making them a target for allergy remedies). NKs (named
by their lack of reliance on antigen-priming) kill virally infected cells and stimulate adaptive immune responses.
Unlike CTLs that rely on MHC expression of viral peptides to kill infected cells, NKs can
recognize infected cells that have low or absent levels of MHC expression
Differentiate This is particularly helpful in viruses like the herpesvirus family and some tumor cells
between Nks that evade CTL recognition by downregulating MHC expression. Likewise, mutation
and CTLs of cancer cells can prevent MHC expression.
mode of
recognizing Other similarities and differences between NK and CTLs
infected cells? ● Recognition of infected cells by NKs is done via receptors which they develop in the
bone marrow whereas CTLs (T lymphocytes) are thymus developed.
● NK Cells share similar T surface molecules such as CD2 and resemble lymphocytes
Describe some
(which is why they are also called large granular lymphocytes).
similarities and
differences
between Nks ● NK cells share the same generic killing mechanisms as CTLs but lack the
and CTLs rearranged T cell receptors that CTLs have (which is why they are innate, not
adaptive).
● NK cells also arise from the same progenitor cells as T & B cells and contribute to
5-15% of lymphocyte population in peripheral blood.
● NKs are also similar to macrophages as both can recognize antigen-coated targets,
however, do not use phagocytosis.
● NKs are activated by cytokines and recognize/kill targets via 20 different specialized
receptors categorized as inhibitory and activating receptors.
NKs kill infected cells with low/absent MHC expression whereas CTLs kill infected cells based on MHC expression
of viral peptides. NKs are bone marrow developed whereas CTLs are thymus developed. They both share generic
killing mechanisms and arise from the same progenitor cells; they share similar T surface molecules and have
similar structures. NKs however do not have rearranged receptors like CTLs. NKs use inhibitory and activating
receptors and can recognize antigone-coated targets but does not kill via phagocytosis.
What are inhibitory Inhibitory Receptors

receptors? Killer Immunoglobulin-like receptors (KIRs) are from the immunoglobulin superfamily
that recognize specific MHC α-chains.
Give some examples. ● C-lectin molecules, NKG2 and CD94, recognize non-classic human
leukocyte antigen E (HLA-E).
How do they function?
● They are inhibitory receptors because their signal dominates all other signals
thus it inhibits NK cells from killing cells with high-level MHC expression
Activating Receptors
What are activating NKs express a specialized receptor FcγRIII which recognizes viral surface antigens
receptors? of infected cells that are bound by IgG and triggers killing of those cells.
● This receptor can be expressed by some macrophages by which IgG acts as
an opsonin to induce phagocytosis.
NK encounters with and recognition (with pattern recognition molecules) of virally

What are the 2
infected cells can result in either outcome:
outcomes of pathogen
recognition by NKs? ● Nk Cells checks for adequate levels of MHC present in the infected cells.
Adequate levels of MHC sends a negative signal to NK to prevent it from
killing the cell. Instead, it shall be killed by a CTL.
● NK Cells recognize infected cells have low levels of MHC and kill the cell
itself.
Inhibitory and activating receptors are what give NKs their preference for
What is responsible MHC-absent cells.
for NKs preferences? ● Also, The cytokine, IFN-γ, maximizes MHC expression and NK cell activity
○ So high levels of MHC is maximized and respond with NK inhibitory
receptors
○ The "danger signal" of low level MHC expression alerts NK cells and
maximizes their activity.
The inhibitory receptors used by NKs are KIRs from the immunoglobulin superfamily which recognize alpha chains
of MHC and the C lectin molecules recognize non-classic human meukocyte antigen e. They are inhibitory because
their signals prevent MHC killing. The activating receptor is FcγRIII which recognizes viral suurface antigens bond by
IgG. If the cells express adequate MHC, they are killed by CTLs, if they express low or absent MHC they are killed
by NKs. Interferon-gamma maximizes both MHC expression and NK activity.
How do NK cells NK Cells are also important during pregnancies:

function in ● Uterine NK present is responsible for protecting the uterus and fetus from
pregnancies? viral infections.
● The Maternal and Paternal (foreign HLA) MHC are expressed in the
placenta, and prevent NKs from attacking fetal tissues.
○ Origin of MHC does not matter, once MHC is expressed, NKs are
inhibited.
● If CTLs were here instead, they would only be able to attack infected cells if
they express antigens and they would cause an allogenic reaction by
attacking placental cells that express paternal (foreign) MHC. (Similar to a
transplant reaction).
What are the effector Effector Mechanisms of NKs and CTLs

mechanisms of NKs Both cells use identical cytotoxic mechanisms which are: Perforin, granzyme and
and CTLs? Fas ligand (FasL) expression and secretion of TNF to induce apoptosis.
Both cells also secrete immunoregulatory cytokines like IFN-γ, to promote TH1
inflammatory responses.
Perforin
What is perforin and This is contained in the cytotoxic granules within NKs and CTLs.
how does it function? ● Upon activation of these cells, the actin cytoskeleton reorganizes so that the
perforin is at the cell surface.
● The preforin polymerizes to form a pore which is inserted into the target cell’s
membrane.
● This allows salts and water to enter the cell and gives granzyme access to
the cytoplasm.
What is granzyme and Granzyme

how does it function? ● This consists of three separate proteolytic enzymes.
● The activated cytoskeleton transport and transfer the enzymes to the target
cell.
● The enzymes degrade the target cell proteins and activate the caspase
enzyme system to trigger apoptosis.
During pregnancies, uterine NK cells protect the uterus and fetus from viral infections by inhibiting attacks on fetal
tissues through the expression of maternal and paternal MHC in the placenta. The origin of MHC becomes irrelevant
once expressed, preventing NK cell activity. NK cells and CTLs share identical cytotoxic mechanisms, utilizing
perforin, granzyme, and Fas ligand expression, along with TNF secretion to induce apoptosis. Perforin, found in
cytotoxic granules in both cell types, forms a pore in the target cell's membrane, facilitating granzyme access to the
cytoplasm and triggering apoptosis through protein degradation and caspase activation.
What is FasL and how Fas Ligand (FasL)

does it function? FasL is an apoptosis inducer used by NKs and CTLs and is expressed increasingly
during the activation of these cells.
● It is used to kill infected cells and tumor cells when the FasL binds to the Fas
on the target cells which triggers intracellular mechanisms leading to
apoptosis.
● T Cells may also express Fas and become targets of Fas-mediated killing if
What cells express
they enter areas where cells express FasL (like immune-privileged areas:
Fas?
BET- brain, eyes, testes).
● Fas and TNF receptors are from the same family; both result in apoptosis
What is the relation
(TNF also result in other cellular changes and can be bound to an immune
between Fas and TNF
receptors? cell or not).
As innate cells, both macrophages and NKs recognize families of pathogens

Describe the effect of (bacteria, viruses, fungi, protozoa/parasites) but not specific antigens.
pathogen recognition ● Upon recognition, they attempt to kill pathogens but also secrete cytokines to
on cytokine secretion. alert adaptive immune system and trigger TH1 responses.
How does this affect ● The cytokine IFN-γ secreted y NKs stimulate TH1 and inhibits TH2.
TH response?
● TH1 responses are preferred because they are effective at dealing with
Which TH response is intracellular infections and provide immunologic memory for stronger
preferred and why? immune responses against possible reexposure to the same pathogen.
Apoptosis in the Immune System

What is apoptosis? Apoptosis is the process of programmed cell death due to physiologic processes like
the caspase enzyme; the subsequent apoptotic cells are removed by phagocytes
without causing inflammation.
What can trigger ● Destruction during cell development or the actions of complement, Tcells.
apoptosis? NKs, mast cells and eosinophils can lead to apoptosis.
What is the result of ● The result of apoptosis is DNA breakdown (by caspase and DNAase) but the
apoptosis? cell membrane remains intact. Apoptosis is usually beneficial.
Fas Ligand (FasL) serves as an apoptosis inducer expressed during the activation of NKs and CTLs, leading to
apoptosis in infected and tumor cells through binding to Fas on the target cells. T cells expressing Fas can also
undergo Fas-mediated killing, particularly in immune-privileged areas like the brain, eyes, and testes. Fas and TNF
receptors, belonging to the same family, both induce apoptosis, with TNF additionally causing other cellular changes
and having the potential to bind to immune cells. Innate cells like macrophages and NKs recognize pathogen
families, secrete cytokines to alert the adaptive immune system, and stimulate TH1 responses through the cytokine
IFN-γ, promoting immunologic memory against intracellular infections.
Necrosis, however, is
spontaneous/inadvertent cell death due to metabolic trauma or insults (like hypoxia or
What is necrosis? toxins) which activates the complement cascade and produces an inflammatory response.
It also does not result in DNA fragmentation like in the case of caspase and
What does it result DNAase.
in?
Apoptosis are necessary in various functions:
● Pregnancies: It is responsible for tissue remodeling during embryonic
development, for example, in the developing vascular system –thus it influences
the shape of the developing faces.
How does apoptosis ● Immune Responses: It is responsible for removing self-reactive/autoreactive T &
impact pregnancies, B cells from the adaptive immune system but also for removing redundant
immune responses lymphocytes after an immune response.
and pathologic ● Pathologic Processes: Apoptotic debris that is not properly cleared by
processes? phagocytes can become immunogenic (meaning it can elicit an immune response)
leading to autoimmune diseases like SLE. Some infections like HIV can induce
apoptosis in immune cells (CD4+ T Cells).
How does defective

Defective Apoptosis occurs in B cell clones with increased levels of Bcl-2 due to
apoptosis occur?
mutations or chromosome translocations thus preventing them from undergoing apoptosis.
This can lead to B cell malignancy.
Give an example of
a circumstance. Some herpesvirus like EBV evades apoptosis by producing a Bcl-2-like protein which
prevents apoptosis in B cells infected with the virus, thus contributing to malignancy.
Necrosis is spontaneous cell death triggered by metabolic trauma or insults, inducing an inflammatory response and
activating the complement cascade, unlike apoptosis which does not result in DNA fragmentation. Apoptosis plays
crucial roles in tissue remodeling during embryonic development, regulating the immune response by eliminating
self-reactive cells, and clearing redundant lymphocytes post-immune response. However, uncleared apoptotic debris
can lead to immunogenic responses, contributing to autoimmune diseases. Defective apoptosis, observed in B cell
clones with elevated Bcl-2 levels due to mutations or chromosome translocations, may prevent proper cell death,
potentially resulting in B cell malignancy.
Chapter 23: Inflammation
What are the clinical Inflammation can be described as:

and histological Clinically: the presence of redness, swelling and pain
definitions of Histologically: the presence of edema fluid accompanied with tissue infiltration by
inflammation? white cells (specific adaptive and innate cells).
Acute Inflammation is the result of innate and adaptive immunity clearing acute
What is acute
infections:
inflammation?
List some features of ● Acute infections last a few days and rarely cause death.
it. ● They rely mainly on innate immunity but also TH1 and TH17 cells.
Give an example of an ● These include infections like influenza and staphylococcal abscesses/boils.
acute infection.
What is chronic Chronic inflammation is a result of acute infections persisting due to failure to clear
inflammation? pathogens/stimulus.
What is a feature of it? ● Chronic inflammation is based on the host cells and pathogens involved
● For example, In Acute infection, hepatitis B, viral mutations allow evasion
Give an example of an
from T cells which causes the infection to persist and become chronic
infection becoming
chronic. hepatitis with inflammation in the liver.
Both forms of inflammation can contribute to autoimmune disease.
Pyogenic Reactions:
What are pyogenic Acute reactions to extracelluar bacterial infections cause pus or yellow sputum
reactions? formation.
● This pyogenic reaction takes a few hours to form pus.
What are the features ● The yellow colour is due to neutrophil granules (and dead neutrophils).
characteristic of
● They may cause severe damage long term but are resolved with minimal
pyogenic reactions?
scarring.
● For example:
Give an example of a ○ Staphylococcus causes pustules and abscesses on the skin.
pyogenic reaction. ○ Haemophilus and pneumococcus (infection in the chest) cause
yellow sputum.
○ Meningitis (Neisseria meningitidis) also causes pus formation.
nflammation is clinically characterized by redness, swelling, and pain, while histologically, it involves edema fluid and
tissue infiltration by white cells from both adaptive and innate immune responses. Acute inflammation arises from
innate and adaptive immunity working to clear short-lived infections, such as influenza and staphylococcal
abscesses, with involvement of innate and adaptive immune cells. Chronic inflammation occurs when acute
infections persist due to an inability to clear pathogens, the nature of which determines the specific cells and
inflammatory response. Both acute and chronic inflammation can contribute to autoimmune diseases, highlighting
the complex interplay between the immune system and inflammatory processes.
What are Granulomatous Reactions:

granulomatous Chronic intracellular bacterial infections that persist may lead to granuloma formation
reactions? (collections of macrophages surrounded by T Cells coordinated by TH1 cells).
● The T cell involvement gives granulomata’s adaptive immune characteristics
What gives like antigen specificity and recall responsiveness.
granulomata its
● This granulomatous reaction is called delayed hypersensitivity (for example
characteristics?
M. tuberculosis)
How long does
formation take? ● Granulomata formation takes 2-3 days because of the T cell response time.
Diffuse Inflammation and Edema
What is meant by Diffuse Inflammation is caused by chronic viral infections while macrophages and
diffuse inflammation? T Cells are present and it is mediated by TH1 cells.
● This follows acute inflammation from antiviral activity where the inflammation
When does it occur persists (failure to clear pathogen).
and what is the result?
● This can also cause damage to host organs.
What is edema? Edema is the result of acute inflammation mediated by mast cells.
When it becomes chronic, it is mediated by both mast cells and eosinophils. For
example, schistosomiasis.
What is the purpose of Cytokine Network

the cytokine network? Cytokine Network (and CD4+ T Cells) refers to interactions between cytokines from
macrophages and eosinophils that initiate acute and chronic inflammatory
responses.
What cytokines do Macrophages: IL-1, TNF and granulocyte-macrophage colony stimulating factor
macrophages (GM-CSF).
secrete? These cytokines are responsible for:
● Activating the acute phase response
What are the effects of ● Promoting narrow production of monocytes and neutrophils.
the cytokines? ● Increasing adherence of leukocytes to local epithelium. (TNF and IL-1)
Chronic intracellular bacterial infections can lead to granuloma formation, characterized by collections of
macrophages surrounded by T cells coordinated by TH1 cells in a delayed hypersensitivity reaction, as seen in
conditions like M. tuberculosis. Diffuse inflammation, associated with chronic viral infections and mediated by TH1
cells, persists beyond acute inflammation, potentially causing organ damage. Edema, resulting from acute
inflammation mediated by mast cells, becomes chronic when both mast cells and eosinophils are involved, as
observed in schistosomiasis. The cytokine network, involving interactions between macrophages, eosinophils, and
CD4+ T cells, initiates both acute and chronic inflammatory responses through the release of cytokines like IL-1,
TNF, and GM-CSF, contributing to the activation of the acute phase response and promoting leukocyte adherence to
local epithelium.
What chemokines do Macrophages also secrete chemokines which release chemotactic signals for
macrophages secrete leukocytes to follow as well as:
and what are their ● IL-1: activates T cells along with costimulatory molecule CD40
effects? ● IL-2: activates TH1 and NK cells
When NK cells and TH1 receive macrophage cytokines, they secrete more TNF and
What effects do
also IFN-γ, the latter is used to:
interferon gamma has
when secreted by NK ● Increase expression of major histocompatibility complex (MHC) on
and TH1 cells? macrophages and other local cells
● Increase antigen processing through proteasomes in macrophages
● Induce macrophage maturation
● Increase NK cell activity
● Inhibit TH2 cells
● Cause mild antiviral effects
IFN-γ affects macrophages by TH1 cell activity through antigen presentation and
How does
cytokine expression.
interferon-gamma
affect macrophages? So now there is a positive feedback loop between macrophages’ IL-12 and
TH1s’ IFN-γ to drive granuloma formation until all phagocytes are cleared
out. Thereafter, T cell stimulation stops and IFN-γ levels falls, macrophage
costimulation is reduced and T Cells undergo apoptosis.
What effect does the The Cytokine Network controls intracellular infections, especially mycobacterium
cytokine network have which includes M.tuberculosis (host-adapted bacteria) and harmless mycobacteria
on intracellular (opportunist/atypical).
infection? Opportunist causes disease when the cytokine network fails:
● Mutations in IL-12, IL-12 receptor or IFN-γ receptor genes making the patient
In what circumstances prone to mycobacterial infections
does the cytokine ● Drugs like monoclonal anti-TNF antibodies used for rheumatoid arthritis
network fails? increase mycobacterial infection risks
● HIV infections cause mycobacterial infections (like Tuberculosis in early
stages and opportunists in later stages) as it damages T cells and
macrophages.
Macrophages release chemokines and cytokines like IL-1 and IL-2, activating T cells, TH1 cells, and NK cells. NK
cells and TH1 cells respond with increased TNF and IFN-γ secretion, promoting MHC expression, antigen
processing, macrophage maturation, and mild antiviral effects. IFN-γ, in a positive feedback loop with macrophages'
IL-12, drives granuloma formation. Once phagocytes are cleared, T cell stimulation ceases, IFN-γ levels drop,
macrophage costimulation reduces, and T cells undergo apoptosis, concluding the immune response.
What receptors does Tuberculosis

M. tuberculosis bind M. tuberculosis binds to TLRs 2 and 4 (which recognize mycobacterial lipoproteins
to? and polysaccharides) to stimulate macrophages, phagocytosis and secretion of
What does it result in? inflammatory mediators, such as IL-12 and nitric oxide as well as TNF and IFN-γ,
(stimulation and which stimulate the formation of granuloma.
secretion).
● The Mycobacterial peptides presented by macrophages elicit strong TH1
responses.
How does M. M. tuberculosis, like most mycobacteria, have waxy coats that block the effects of
tuberculosis evade phagocyte enzymes and they secrete catalase to prevent the effects of the oxidative
innate immune burst.
responses? ● In response to mycobacteria evasion, macrophages seal off mycobacteria
How do macrophages inside phagosomes with the help of T cells in the form of TH1 cytokines such
respond to their as IFN-γ.
evasion?
● In primary TB infections, macrophages at the granulomata mature into giant
Differentiate between
and epitheloid cells (mediated by IFN-γ). The infected macrophages are
primary, miliary, latent
and postprimary TB sealed off and the center of the granulomata can become hypoxic and
infections. necrotic with a characteristic, cheese-like appearance.
● In young or immunodeficiency patients, Miliary TB occurs where widespread
infections develop.
● Latent TB infections occur when mycobacteria survive in side macrophages
or other cells several years after primary infection.
What does an ● Patients with an overzealous reaction to primary TB infection produces
overzealous reaction excessive TNF, causing extensive local tissue damage and are able to infect
to TB cause? others.
● Postprimary (reactivation) TB occurs if macrophage function is moderately
impaired, usually as a result of high corticosteroid doses, malnutrition or HIV
How are antibodies infections.
not helpful against TB ● Antibodies are negligible in TB, especially since preexisting antibodies do
infections? not prevent TB infection. The mycobacteria resides in cells and evades
antibody-mediated destruction.
Mycobacterium tuberculosis stimulates macrophages through TLRs 2 and 4, inducing phagocytosis and the
secretion of inflammatory mediators, fostering granuloma formation. The waxy coats of mycobacteria thwart
phagocyte enzymes, and they secrete catalase to counteract the effects of oxidative burst. Macrophages respond by
sealing off mycobacteria within phagosomes with the help of TH1 cytokines like IFN-γ. In primary TB infections,
granulomatous reactions lead to the formation of giant and epitheloid cells in the hypoxic and necrotic centers, while
latent TB infections persist as mycobacteria survive inside cells.
Describe the Hepatitis Hepatitis B Virus Infection

B Virus Infection The virus causes hepatitis that often leads to cirrhosis and liver cancer (hepatoma).
● HBV replicates only in hepatocytes (parenchymal cells in the liver) but does
not damage these cells directly; the virus is not cytopathic (able to cause
structural changes to host cell).
What is the immune
Immune Response to HBV:
response to HBV?
Once the antibodies for the HBV surface protein (HBsAg) are present when the virus
first enters the blood, the antibodies will bind on to the virus and prevent it from
attaching itself to hepatocytes.
How are the ● Thus anti-HBsAg can protect the liver from infection.
antibodies acquired? ● HBV vaccinations accomplish this but anti-HBsAg can also be given as
passive immunity after known exposure to HBV.
● If HBV is actively replicating in the liver, antibodies become less important
than the cellular immunity mediated by TH1 cells.
○ Antibodies play a more important role in diagnosis.
What is the caveat to
○ The cellular immunity is important for patients without protective
antibodies against
HBV? antibodies who already have the virus replicating in their
hepatocytes.
● However, in established infections, antibodies still provide a degree of
control over HBV.
○ This is confirmed since drugs or diseases that prevent antibody
production can lead to a flareup of HBV replication
HBV is susceptible to the antiviral effects of Interferons:

How do IFNs and ● The specific immune system responds to the infection with a TH1-type
adaptive immunity
response, and the hepatitis B–specific CD4+ and CD8+ T cells migrate to
affect HBV infections?
the liver.
● These T cells secrete IFN-γ and TNF which promote the inflammatory
response and shows that the antiviral effects of IFN-γ inhibit viral replication.
What are the effects of ● Infected patients develop transient hepatitis, however, most infected patients
transient hepatitis? manage to suppress viral replication through the antiviral effects of IFN-γ.
Transient hepatitis is life-threatening in less than 1% cases.
Hepatitis B Virus (HBV) infection, leading to cirrhosis and liver cancer, specifically replicates in hepatocytes without
causing direct damage. Antibodies against the HBV surface protein (HBsAg) play a protective role by preventing
virus attachment to hepatocytes, a mechanism employed by both vaccinations and passive immunity through
anti-HBsAg administration. Cellular immunity, mediated by TH1 cells, becomes crucial when HBV actively replicates
in the liver, while antibodies primarily aid in diagnosis. Interferons, triggered by a TH1-type response, exhibit antiviral
effects, particularly through IFN-γ and TNF, suppressing viral replication and causing transient hepatitis,
life-threatening in less than 1% of cases.
What effect does IFN-γ has potent stimulating effects on inflammation, and a mild inflammatory
Interferon-gamma response develops, during which some hepatocytes are damaged by the immune
have on inflammation? response rather than by the virus itself.
● The result is acute hepatitis.
What is the result? ● In the majority of patients, viral replication is subsequently controlled but
even though the virus is not eradicated, the T-cell responses are enough to
minimize virus replication so that the patient stops being infectious to other
individuals.
The virus does not always clear this way due to various factors like:
Why is the virus not ● If the initial inoculums (material used to cause immunization) of the virus was
always cleared? particularly large.
● Exposure to HBV at a very early age (a type of tolerance).
● Host factors (like the patient’s HLA type).
In these cases, the inflammatory response persists (chronic hepatitis) even though
How does chronic
the response cannot inhibit viral replication. Even so, chronic hepatitis B infection
inflammation occur?
does not produce granulomata.
● The production of IFN-γ during these infections can be both beneficial and
What effect does problematic as it is capable of inhibiting viral replication but it will promote a
interferon-gamma chronic inflammatory response that results in chronic active hepatitis.
have on chronic
hepatitis? ● This is due to the recruitment of NK cells, macrophages, and T cells that are
Why does this effect not even specific for HBV, leading to chronic inflammation inside the portal
occur? areas and causing tissue destruction which scars.
What indicates the ● These scars can lead to liver cirrhosis and eventually liver cancer. When
damage done was a inflammation causes more damage than the actual virus, that it is
result of characteristic of exaggerated/overzealous reactions (hypersensitivity).
hypersensitivity?
IFN-γ exerts potent stimulating effects on inflammation, contributing to a mild inflammatory response during acute
hepatitis in which some hepatocytes are damaged by the immune response rather than the virus. While the majority
of patients control viral replication after this phase, the virus is not always cleared due to factors like large initial viral
inoculums, early age exposure, and host factors such as HLA type. In cases where clearance is incomplete, chronic
hepatitis may ensue, marked by persistent inflammation that does not inhibit viral replication. Chronic active
hepatitis, lacking granulomata, results in the production of IFN-γ, inhibiting viral replication but promoting chronic
inflammation that can lead to liver cirrhosis and, ultimately, liver cancer. Exaggerated reactions, indicative of
hypersensitivity, occur when inflammation causes more damage than the virus itself.
Describe reinfection of Individuals who have been infected with HBV but have successfully suppressed viral
HBV. replication can be compromised, especially if they have latent infection.
● For example, monoclonal Abs against B cells or against TNF used for
treatments of some diseases, when administered to a patient with previous
HBV can reactivate the infection.
Cytokines and Granuloma formation during inflammation has negative effects like:
What effects does
granulomata have on ● TNF causing weight loss
a patient during ● Excessive granuloma formation in the lung in response to M. tuberculosis.
inflammation? ● Lung cavities form due to dead, necrotic granulomata material being
coughed up which can spread TB from person to person if the mycobacteria
is contained in it (open TB).
● The dead granulomata is the result of poor blood supply to its center.
● Fibrosis and cirrhosis from hypersensitivity reactions of the immune system
in response to Hepatitis B infection.
Individuals who have successfully suppressed HBV replication can face risks, particularly if latent infection persists.
Treatments involving monoclonal antibodies against B cells or TNF, used for certain diseases, can reactivate HBV
infections in previously infected patients. Cytokines and granuloma formation during inflammation can have adverse
effects, including TNF causing weight loss. Excessive granuloma formation in response to M. tuberculosis can lead
to lung cavities formed by necrotic granulomatous material, potentially spreading tuberculosis from person to person
in cases of open TB. The dead granulomata result from poor blood supply to their centers. Additionally,
hypersensitivity reactions to Hepatitis B infection can lead to fibrosis and cirrhosis.
Chapter 24: Cytokines in the Immune System
What are cytokines? Cytokines are soluble messenger molecules responsible for communication
between the immune cells of the innate and adaptive immune systems.
They are usually secreted by immune cells, especially during the immune response.
What cells can secrete However, nonimmune cells like epithelial cells can secrete Type 1 Interferons (IFNs)
cytokines?
and Tumor Necrosis Factor (TNF).
Since they are usually secreted in response to infections, they are secreted
How long does transiently and once the infection is eliminated, cytokine secretion falls.
secretion last? ● For example, Il-2 is only secreted for 8 hours by activated T cells and any
longer can result in a hypersensitivity reaction.
What is the purpose of Inhibitory cytokines are also secreted at the end of an immune response to
inhibitory cytokines? prevent the response from continuing such as IL-10 and TGF-β.
They are constitutively secreted (constantly secreted at a low level, making it

What is constituitive
impossible to detect in blood), but the effects vary according to the immune system:
secretion?
● Adaptive immune cells secrete cytokines at low levels which has paracrine
effects (affecting neighbouring cells) and autocrine effects (affecting self),
What effect does
cytokine secretion and is necessary to maintain adaptive immunity’s specificity.
from adaptive cells
○ For example, IL-2 secreted by T Cells induces T cell proliferation
have?
Give an example. (autocrine effect). If it were secreted in high levels, it may activate
cells that did not recognize any antigens.
● Innate immune cells secrete cytokines at low levels over a short range but
What effect does can secrete them at high levels where they are detected in blood. At high
cytokine secretion levels, they act as endocrine hormones.
from innate cells
have? ○ For example, Chemokines are secreted at short range to attract
Give an example. neutrophils to the site of infection. IL-1, IL-6 and TNF secreted at
high levels during an acute-phase response can cause induction of
fever.
Cytokines, essential for immune cell communication, are primarily secreted by immune cells in response to
infections, with nonimmune cells like epithelial cells also contributing Type 1 Interferons (IFNs) and Tumor Necrosis
Factor (TNF). Their transient secretion occurs during the immune response and diminishes upon infection clearance;
for instance, IL-2 is only secreted for a limited time by activated T cells to avoid hypersensitivity reactions. Inhibitory
cytokines, such as IL-10 and TGF-β, are later secreted to curb prolonged immune activation. Constitutively secreted
at low levels, cytokines exhibit different effects based on the immune system type—adaptive immune cells use
paracrine and autocrine effects to maintain specificity, while innate immune cells release them at higher levels,
acting as endocrine hormones. This distinction is illustrated by chemokines attracting neutrophils locally and IL-1,
IL-6, and TNF inducing fever during an acute-phase response when released at high levels
What is the acute Acute phase responses are the physiological process after the onset of infection,
phase response and inflammation or trauma: fever, vascular permeability, high white blood cell count, loss
what does it cause? of appetite and increased production of acute phase proteins (C-reactive protein,
MBL).
Cytokines also have two important characteristics:

What is meant by
● Redundancy: Several cytokines are secreted during a response and they
cytokine redundancy?
Describe its share similar effects which allow them to synergize and have a greater sum
importance. impact.
○ (This is important clinically as attempting to bock the cytokines will
not always produce clinical outcomes, using Anti-TNF antibodies
may not prevent rheumatoid arthritis since IL-1 also causes it).
What is meant by ● Pleiotropism: Many cytokines affect several different types of cells.
cytokine pleiotropism? ○ (This is clinically important as interferon-alpha can treat Hepatitis B
but it can also trigger acute-phase responses which would make
patients unwell).
Besides synergizing innate and adaptive responses, cytokines can also inhibit each
Give an example of
other.
cytokines inhibiting
each other For example, IFN-γ promotes T-helper 1 (TH1) cell responses and also
inhibits the development of TH2 responses, mediated by IL-4
Cytokine Receptors and Signaling Molecules:

How are the cytokine The receptors for cytokines are also expressed transiently by activated cells in order
receptors expressed? to prevent inappropriate responses of the immune system.
Cytokines use receptors that belong to one of these three types:

What are the cytokine ● Common Cytokine Receptor Family (Hemopoietin Receptors)
receptors? ● Chemokine Receptor
● TNF receptor
Acute phase responses, initiated by infection or inflammation, manifest as physiological changes including fever,
increased vascular permeability, elevated white blood cell count, and heightened production of acute phase proteins.
Cytokines, crucial signaling molecules in immune responses, exhibit redundancy and pleiotropism, presenting
challenges in clinical interventions as blocking one cytokine may not produce desired outcomes due to synergistic
effects and varied impacts on different cell types. Moreover, cytokines can exert inhibitory effects on each other,
influencing the balance of immune responses. The receptors for these cytokines, expressed transiently by activated
cells, play a crucial role in preventing inappropriate immune system responses and belong to three main types: the
Common Cytokine Receptor Family (Hemopoietin Receptors), Chemokine Receptors, and TNF receptors
Describe the structure Most cytokines like growth factors and interferons use the common receptor. The
of the common receptors consist of one or more transmembrane molecules with extracellular
cytokine receptor. domains (conferring specificity for particular cytokines).
● The receptors for IL-2, IL-4, and IL-7 consist of three separate polypeptide
Describe the structure
chains but share a common γ-chain.
oof interferon
receptors. ● They are upregulated in expression when the cell is activated and is then
spread across the cell.
● When a cytokine binds with its receptor, it causes aggregation of the

What are Janus
receptors at the cell surface. A tyrosine kinases, Janus kinases (JAKs), is
kinases?
associated with the cytoplasmic part of the receptor and it remains inactive
until the aggregation occurs.
What are signal ● Once activated, it phosphorylates a transcription factor called signal
transducers and transducers and activators of transcription (STATs) which form a dimer after
activators of phosphorylation, migrate to the nucleus, and activate transcription of specific
transcription? genes until the immune response is over.
How do JAKs and ● JAKs and STATs vary according to cytokine and receptor: IL-2 activates
STATs vary? JAK5, STAT1 and STAT3 which initiate T Cell proliferation.
Cytokines like growth factors and interferons typically utilize a common receptor, consisting of one or more
transmembrane molecules with extracellular domains for specificity. Receptors for IL-2, IL-4, and IL-7 have three
separate polypeptide chains but share a common γ-chain. Upon cell activation, these receptors are upregulated and
spread across the cell. When a cytokine binds to its receptor, it triggers receptor aggregation at the cell surface,
activating Janus kinases (JAKs) associated with the receptor's cytoplasmic part. Activated JAKs then phosphorylate
the transcription factor STAT (signal transducers and activators of transcription), initiating gene transcription until the
immune response concludes.
What are Chemokines are a cytokine family responsible for attracting cells to inflamed tissues and
chemokines? leukocyte homing.
● The chemokine receptors are α-helices that span the cytoplasmic membrane seven
Describe the times and upon binding chemokines, the receptors catalyze the replacement of
chemokine receptor. guanosine diphosphate (GDP) by guanosine triphosphate (GTP).
TNF can be secreted or membrane-bound but can also be cleaved from its secreting cell to
cause local or remote effects.
What is tumor
necrosis factor? ● Cell-bound and Cell-free TNF uses a special family of receptors mainly one of two
possible receptors). The TNF are trimers as well as their receptors.
What ● There is also: CD40 and CD40-ligand (CD154), costimulatory pair from the TNF-TNF
receptor-ligands exist ligand family involved in communication between T Cells and B Cells/APCs. There is
in this family? also Fas and Fas ligand (FasL).
The effects of TNF depends on its target cell which it binds to:
How do the effects of ● Binding to Infected Cells: Induces apoptosis through caspases and the death domain
TNF vary according ● Binding to Macrophages and Endothelial Cells: Induces transcription of genes by
to their binding
engaging a special set of adaptor molecules which activate Nuclear Factor kappa B
target?
● Fas-FasL: Induces apoptosis in target cells
● CD40/CD154: Induce gene transcription and communication between T cells and B
Cells/APCs.
Chemokines, a subset of cytokines, are essential for attracting cells to inflamed tissues and guiding leukocyte
homing. Chemokine receptors, comprising α-helices spanning the cytoplasmic membrane seven times, activate
guanosine triphosphate (GTP) upon binding, facilitating cellular responses. Tumor Necrosis Factor (TNF), existing in
secreted, membrane-bound, or cleaved forms, interacts with specific receptors, including CD40 and CD40-ligand
(CD154), to mediate diverse effects. TNF's impact varies based on the target cell, inducing apoptosis in infected
cells, activating gene transcription in macrophages and endothelial cells, and facilitating communication between T
cells and B cells/antigen-presenting cells through CD40/CD154.
Cytokines in Immune Responses

Acute Inflammation: Initial Response to Infection
● Cytokines are secreted as danger signals when innate immune cells

Describe the role of recognize the PAMPs of invading pathogens.
cytokines in immune
responses? ● Cytokines (IL-1, TNF, G-CSF, IL-6) in response to TLR detecting extracellular
pathogens are secreted to stimulate local inflammation and develop an
acute-phase response.
How does it cause
acute inflammation? ● Cytokines (chemokines, IL-8) secreted by macrophages and local cells at
inflame sites are responsible for attracting neutrophils to site of infection.
How are TH cells ● Cells at the site of infection also secrete IL-23 to stimulate TH17 priming and
affected by cytokines upon reexposure to the same pathogen, TH17 secretes IL-17 to attract
during this response?
neutrophils and stimulate secretion of antimicrobial peptides by endothelial
cells.
How do interferons ○ Antimicrobial peptides are necessary for disrupting bacterial cell
affect acute phase membranes
responses? ● Type 1 cytokines (interferons) have antiviral effects and enhance antigen
presentation of viral antigen peptides and enhance TH1 responses. They
also trigger acute-phases responses.
T-Cell Priming
How do cytokines
● This occurs in the lymph node that drains the site of infection where T cells
affect T Cell priming?
represented with antigens by dentritic cells which activates TH cells (if the
correct receptor and costimulatory surface molecules –CD40, CD80,
intercellular adhesion molecules, are used).
● Costimulatory Cytokines (IL-1, Type 1 IFNs) are secreted by APCs to help

initiate T-cell responses.
What are the effects of
T Cell priming? ● Activated TH cells upregulate IL-2 receptors and secrete IL-2 but will not
proliferate until IL-2 binds to its own receptor (autocrine) or receptors of
neighbouring T Cells (paracrine).
During acute inflammation, cytokines, including IL-1, TNF, G-CSF, and IL-6, serve as danger signals when innate
immune cells recognize pathogen-associated molecular patterns (PAMPs). This prompts the secretion of cytokines
to stimulate local inflammation and initiate an acute-phase response in response to Toll-like receptors detecting
extracellular pathogens. Chemokines and IL-8 are then released at the inflammation site to attract neutrophils, while
IL-23 facilitates TH17 priming. Upon reexposure to the pathogen, TH17 secretes IL-17, recruiting neutrophils and
prompting the release of antimicrobial peptides by endothelial cells, disrupting bacterial cell membranes. T-cell
activation leads to the upregulation of IL-2 receptors and IL-2 secretion in activated TH cells.
Development of Specialized T-Cell Responses

How do T Cells impact Gut Immunity
immunity in the gut? ● Gut-derived T cells secrete transforming growth factor beta which induces Ig
class switching from IgM to IgA (for mucosal immunity).
● TGF-β is anti-inflammatory, it can induce T Cells to become Tregs and
inhibits the effects of most T-cell populations, macrophages and
proinflammatory cytokines –this is done to skew the immune response in the
gut to an IgA dominated response.
What is the role of TH17 Responses

TH17 in T Cell ● IL-23 is secreted by innate immune cells in response to extracellular
responses? pathogens which stimulates TH17 cell (which secretes IL-17) needed for
attracting neutrophils.
TH1 Responses
● APCs secrete IL-12 and type 1 IFNs in response to intracellular pathogens
What is the role of
which induces T-Cell transcription factor T-bet. This leads to IFN-γ secretion
TH1 in immune
responses? and a TH1 cell which favours the IgG production needed for phagocytosis
(by phagocytes).
● IL-6 also encourages IgG production by B Cells.
If intracellular infection persists, TNF is secreted at high levels resulting in
granuloma production.
TH2 Responses
What is the role of ● GATA3 (T cell transcription factor) is induced in response to worm infections,
TH2 in immune which causes IL-4 secretion that favours IgE production. The IgE activates
responses?
mast cells which produces more IL-4.
● Worm infections favour TH2 responses and TH2 cells secrete other
cytokines, IL-5 and the chemokine eotaxin which continues the TH2
response by stimulating mast cell and eosinophil maturation.
What is the role of Regulatory T Cells

Tregs in immune ● Tregs secrete IL-10 and transform growth factor beta to inhibit responses to
responses? self-antigens and encourage peripheral tolerance.
Gut-derived T cells play a pivotal role in mucosal immunity by secreting transforming growth factor beta (TGF-β),
promoting IgA dominance and inducing regulatory T cells (Tregs). TH17 responses are stimulated by IL-23 in
response to extracellular pathogens, leading to IL-17 secretion and neutrophil attraction. TH1 responses, induced by
IL-12 and type 1 interferons, result in IFN-γ production and IgG formation crucial for phagocytosis. TH2 responses,
activated by GATA3 in worm infections, lead to IL-4 secretion, IgE production, and mast cell activation. Regulatory T
cells contribute to peripheral tolerance by secreting IL-10 and TGF-β.
What cytokines End of the Immune Response

mediate the end of an After the pathogens are eliminated, the danger signals falls and IL-1, type 1 IFNs
immune response? and TNF falls also.
● Less antigen is available for presentation so T-cell stimulation declines and
subsequently, cytokines secreted are lessened and cytokine receptors
expression is reduced to low levels.
What are the effects of
these cytokines? ● IL-2 falling causes T cells to produce less Bcl-2 so apoptosis can occur, but
memory T Cells number are maintained by constitutive secretion of IL-7.
Neutrophil numbers are maintained by constitutive secretion of GCSF.
Inflammatory cytokines are switched off until the next infection.
Clinical Uses for Cytokines and Cytokine Blockade

How are cytokines ● Unlike blood levels of hormones, blood levels of cytokines are not measured
used clinically? in routine clinical practice. This is because cytokines are generally short
ranged, and do not spill into blood (for example, they are limited to germinal
center in the lymph node). Hormones circulate within the blood.
Compare their use
with hormones. ● However, in cases like toxic shock, high levels of TNF or IL-6 are present in
the blood. It is still easier to measure high cytokine levels by measuring
clinical signs such as high fever, low blood pressure or abnormal white cell
count.
● Likewise, in the IFN-γ release assay (IGRA), IFN-γ is not measured in blood
How are cytokine but actually it is measured after it has been secreted by patient cells (vitro).
levels measured?
The endof the immune response involves a decline in danger signals and a subsequent decrease in IL-1, type 1
IFNs, and TNF. As antigen availability diminishes, T-cell stimulation wanes, leading to reduced cytokine secretion
and decreased expression of cytokine receptors. IL-2 reduction prompts T-cell apoptosis, while memory T cells are
sustained through constitutive IL-7 secretion. Neutrophil numbers are maintained by constitutive G-CSF secretion,
and inflammatory cytokines are silenced until the next infection. In clinical practice, measuring blood levels of
cytokines is uncommon due to their short range, and clinical signs like fever, blood pressure changes, or abnormal
white cell count are used as indicators. Instances like toxic shock or the IFN-γ release assay reveal elevated
cytokine levels associated with specific clinical conditions.
Chapter 25: Infections and Vaccines
Organisms Evading the Immune Response

Viruses
● For small RNA viruses that cannot encode proteins to evade immune
How do small viruses responses, they rely on viral mutations (of the RNA genome) and antigenic
evade the immune proteins that change due to these mutations cause evasion of immunologic
response?
memory.
○ For example, Influenza and HIV. HIV mutates rapidly within the
How do large viruses individual whereas Influenza mutates slowly across a population.
evade immune ● DNA viruses are large enough to encode evasion tools in their genome.
responses? ○ For example, herpesvirus can to downregulate MHC expression and
thus, evade adaptive and innate immune cells (especially evading
NKs since innate cells don’t have memory so they can't be primed to
resist herpes infections).
Bacteria:
● Some bacterial pathogens use capsules to evade opsonization by
How do bacteria
complement and phagocytosis during innate immune responses.
evade immune
responses? ○ For example, Streptococus pneumoniae and Haemophilus use a
polysaccharide coating to evade innate responses and infect the
respiratory tract.
Give some examples. ○ Mycobacteria (mycobacteria tuberculosis) use waxy coats to block
phagocyte enzymes, plus they secrete catalase to inhibit the effects
of respiratory burst.
○ Listeria (causing meningitis in pregnant women), secretes

listeriolysin which punches holes in the phagolysosome walls so the
bacteria can enter the cytoplasm, they are not exposed to the toxic
products of the metabolic burst or to proteolytic enzymes.
■ (Phaoglysosome is the fusion of phagosome and lysosomes

during phagocytosis to destroy intracellular pathogens).
How do worms evade
the immune ● Worms coat themselves in host antigens like MHC to evade immune
response? responses and secrete protease inhibitors to block gut enzymes.
Viruses, particularly small RNA viruses like Influenza and HIV, rely on rapid mutations in their RNA genome and
changes in antigenic proteins to evade immune responses. DNA viruses, such as herpesviruses, can encode
evasion tools in their genome, allowing them to downregulate MHC expression and evade both adaptive and innate
immune cells. Bacteria employ various strategies to evade innate immune responses, such as using capsules (e.g.,
Streptococcus pneumoniae and Haemophilus) to evade opsonization and phagocytosis. Mycobacteria, like
Mycobacterium tuberculosis, use waxy coats to block phagocyte enzymes, while Listeria secretes listeriolysin to
enter the cytoplasm and avoid exposure to toxic products. Worms use host antigens and secrete protease inhibitors
to evade immune responses.
What mechanisms Mechanisms of Immunity

modulate primary ● Clearing most primary infections results in sterilizing immunity, as well as
responses? immunologic memory which prevents infections (or at least reduces
symptoms) upon reexposure to the same pathogens.
○ Exception is Tuberculosis, HIV and herpesvirus infections.
● Primary infections are important in childhood as they introduce immunologic
What are the
memory, especially since maternal antibodies would be depleted.
importance of primary
infections and ● However, vaccination allows immunologic memory without symptomatic
vaccines? primary infection.
○ Due to vaccination, smallpox (a lethal infection) has been eradicated
and polio, diphtheria & pertussis is rare.
Passive immunotherapy is the transfer of adaptive immunity (antibodies) from one

What is passive individual to another who has been exposed to a pathogen.
immunotherapy? Antidigoxin Fab fragments are also a type of passive immunity.
Give an example. ● Example, Individuals exposed to tetanus can receive passive
immunotherapy to reduce the risk of infection and a vaccine to
induce memory and prevent future infections.
What is active Active Immunity develops from the immune system being stimulated by antigens
immunity? from an infection or vaccine which produces immunologic memory to prevent
reinfections.
Vaccines can elicit antibody and T cell responses.

Antibodies:
How do antibodies ● These can be neutralizing antibodies that prevent pathogen binding onto
respond to vaccines?
target cells or toxin-release from pathogens
● They can activate complement, and stimulate phagocytosis and NK
cell-mediated killing.
CD8+ T Cells:
How do T Cells ● They secrete IFNs to inhibit viral replication
respond to vaccines? ● They kill infected cells to prevent viral replication
Clearing most primary infections establishes sterilizing immunity and immunologic memory, crucial for preventing
reinfections upon subsequent exposure to the same pathogens. Notable exceptions include tuberculosis, HIV, and
herpesvirus infections, which may persist or undergo latency. Primary infections in childhood are pivotal for
introducing immunologic memory, particularly as maternal antibodies wane. Vaccination, by contrast, allows for the
development of immunologic memory without the symptomatic experience of a primary infection. Both use active
immunity, whereas passive immunity only transfers antibodies. Successful vaccination efforts have led to the
eradication of smallpox and a significant reduction in the incidence of diseases like polio, diphtheria, and pertussis.
Vaccination elicits T cell responses to inhibit viral replication and B cells responses to activate complement and t
prevent pathogens from binding and releasing substances.
1. Live Vaccines
What are live These are vaccines that use nonvirulent organisms that can replicate in the vaccine recipient
vaccines? without causing disease.
● They are the first vaccines to be discovered/developed.
● The nonvirulent organisms usually come from animals that contain the
microorganisms grow in them (nonhuman pathogens)
○ For example, the cowpox virus was used as a vaccine for smallpox. Others
Where do the live include measles and mumps. The consequent antibodies can persist for
organisms come decades after vaccination.
from? ○ The nonvirulent organisms also come from attenuated (weakened) human
pathogens which cannot cause disease. Also, recombinant organisms.
○ The attenuation is caused by direct manipulation of genomes in special
conditions in vitro.
● They can be excreted and passed on to other vaccinated individuals
The advantages of Live Vaccines are due to their ability to replicate:
Describe some ● Replication allows for sustained doses of antigen to be delivered
advantages of live ● Intracellular replication allows antigenic peptides to be delivered to MHC class 1
vaccines molecules which stimulates CTLs.
Live vaccines utilize nonvirulent organisms capable of replicating in the vaccine recipient without inducing disease.
Typically derived from animals or attenuated (weakened) human pathogens, these vaccines were the first to be developed.
Examples include the use of cowpox virus for smallpox vaccination and measles and mumps vaccines. The antibodies
generated can persist for extended periods. Live vaccines offer advantages such as sustained antigen delivery through
replication and the stimulation of cytotoxic T lymphocytes (CTLs) through intracellular replication, promoting a robust
immune response.
What are some Disadvantages of Live Vaccines:

disadvantages of live ● In the case of patients with immunodeficiency, attenuated organisms can still
vaccines? cause infections.
● Occasionally the nonvirulent organisms can spontaneously revert to the
virulent wild-type organisms.
○ In the case of live polio organisms, the attenuated virus differs by 10
base pairs which makes it easy to revert to its wild type. Therefore,
killed polio vaccines are used instead.
● Viral vectors (experimental live vaccine) are viruses intentionally genetically
altered to be safe for humans and to be used as vectors to acquire genes
from another organism to be expressed.
○ For example, canarypox virus is used as a vector for HIV genes.
2. Killed Organisms
What are killed These are vaccines containing killed organisms instead of nonvirulent live
organism vaccines? organisms.
● They are safer than live organisms but not as effective.
How effective are ○ This is because they cannot replicate in vaccine recipients and
they? cannot enter intracellular-antigen presenting pathways.
○ For example, influenza is frequently given as a killed vaccine though
there is a live vaccine available.
Cytokines are crucial signaling molecules in the immune system, facilitating communication between immune cells.
They are mainly secreted by immune cells in response to infections and exert various effects to orchestrate an
effective immune response. While some cytokines, such as IL-2, IL-4, and IL-7, have specific receptors composed of
multiple polypeptide chains, others, like TNF and chemokines, use distinct receptor families. Cytokines play a role in
both innate and adaptive immunity, influencing processes such as inflammation, cell differentiation, and antibody
production. Understanding the intricate network of cytokines is essential for deciphering immune responses and
developing therapeutic interventions for immune-related disorders.
What are subunit 3. Subunit Vaccines

vaccines? These are vaccines containing nonvirulent components (subunits) of pathogens.
● The components are created by destroying virulent organisms, purifying their
subunits and inactivating them so they are nonvirulent.
How are the subunits ● Purified, inactivated components are called toxoids, and are usually
created? bacterial toxins chemically altered to be safe while retaining antigenicity.
○ For example, diphtheria and tetanus toxoid.
● These vaccines can also be prepared using recombinant technology.

(Recombinant vaccines).
○ Hepatitis B vaccine is produced using recombinant virus surface
Describe recombinant
peptides and the antibodies produced in response to it prevents the
and peptide vaccines
virus from attaching to and entering liver cells.
○ Peptide (as a subunit) vaccines may not remain successful.

What immune
response does subunit ● Subunit vaccines primarily elicit an antibody response, where neutralizing
vaccine elicit?
antibodies block toxins’ effects.
● DNA (as a subunit) vaccines are experimental and uses the gene for
immunogenic protein which is coated into gold microspheres and injected
Describe DNA
directly into cells.
vaccines
○ It was successful in mice since antibodies were created which
indicated the DNA was transcribe but not in humans since it is not
possible to provide enough DNA for routinely use.
Subunit vaccines consist of nonvirulent components of pathogens, often created by inactivating and purifying virulent
organisms. The purified components, known as toxoids, can be bacterial toxins chemically altered to be safe while
retaining their antigenicity, as seen in diphtheria and tetanus toxoid vaccines. Recombinant technology is also
employed to produce subunit vaccines, such as the hepatitis B vaccine, which uses recombinant virus surface
peptides. While subunit vaccines predominantly trigger an antibody response, some experimental approaches, like
DNA vaccines, aim to introduce the gene for immunogenic proteins. DNA vaccines have shown success in animal
models, but challenges persist in translating these findings for routine human use due to limitations in providing
sufficient DNA.
What are the Disadvantages of Subunit Vaccines:

disadvantages of ● They have low immunogenicity and shorter antibody responses (years than
subunit vaccines? decades) than live vaccines.
○ In the case of low immunogenicity, an agent called an adjuvant is

How are these used to boost the immune responses to the vaccine.
disadvantages
treated? ○ In the case of the short antibody responses, boosters are given. For
example, tetanus antibodies persist for 10 years after vaccination so
a booster would be needed.
Why are ● Polysaccharides (as a subunit) are poor immunogens because they rely on
polysaccharide T-independent B cell responses and they do not make good vaccines.
vaccines ineffective?
● Polysaccharides must be chemically conjugated to a peptide antigen (for
How is this treated? example, tetanus toxoid) so T cells can respond to the peptide and then
provide help to B cells to respond to the polysaccharide.
○ These are called conjugate vaccines
○ This is important since vaccines rely on immunologic memory and

T-independent B cells do not create memory B cells.
How do subunit and ● They do not enter intracellular pathways so they cannot elicit CTL responses
live vaccines differ in which is necessary for vaccines against intracellular infections like HIV.
performance?
● This is unlike live vaccines that contain intracellular pathogens and can
access intracellular pathways.
Subunit vaccines, which contain nonvirulent components of pathogens, face several drawbacks. One major
challenge is their low immunogenicity, often resulting in shorter-lived antibody responses compared to live vaccines.
To overcome this limitation, adjuvants are employed to enhance immune reactions. Subunit vaccines using
polysaccharides encounter issues, as they rely on T-independent B cell responses, leading to poor immunogenicity.
Conjugate vaccines, which combine polysaccharides with peptide antigens, address this by engaging T cells and
promoting immunologic memory. However, subunit vaccines, including polysaccharide-based ones, lack the ability to
induce cytotoxic T lymphocyte (CTL) responses, limiting their effectiveness against intracellular infections compared
to live vaccines.
Adjuvants
What are adjuvants? These are substances (usually aluminum salts) that increase the immune responses.
Give examples of
some adjuvants and
their vaccines
● They accomplish this by providing PAMPs and DAMPs

(pathogen/damage-associated molecular patterns) to stimulate innate immune
How do adjuvants responses which causes the release of danger signals to drive adaptive immune
boost immune responses.
responses? ○ Alum activates macrophages which secrete inflammatory cytokines and
present antigens to lymphocytes by causing local damage which the
What innate cells macrophages detect (DAMPs). It is not a powerful adjuvant.
respond to aluminum?
● Monophosphoryl lipid (MPL, a recent adjuvant) from Salmonella polysaccharide
is used to trigger TLR-4. Macrophages exposed to MPL increase IL-12 secretion
What effect does MPL and upregulate MHC 2 expression
adjuvant has? ○ These effects increase antigen presentation and skew the immune
What vaccines use response towards TH1. MPL is used in licensed vaccines HPV and
MPL? malaria vaccines.
● Live vaccines do not need adjuvants as they can provide danger signals and
stimulate TLRs by themselves.
Why do live vaccines ○ For example, bacilleCalmette-Guérin (BCG), the live vaccine for
not contain adjuvants? Tuberculosis, produces large quantities of bacterial sugars that Activate
TLRs 2 and 4 (remember live vaccines can replicate).
What adjuvants are ● Killed vaccines contain substances that activate TLRs and act as natural
found in killed adjuvants.
vaccines and ● Subunit and Recombinant Vaccines do not contain natural adjuvants so they
subunit/recombinant require synthetic adjuvants.
vaccines?
Adjuvants are essential components in vaccines, enhancing their efficacy by stimulating innate immune responses.
Aluminum salts, known as alum, are widely used adjuvants that activate macrophages and induce antigen presentation.
Monophosphoryl lipid (MPL), a newer adjuvant derived from Salmonella polysaccharide, triggers TLR-4, promoting
increased IL-12 secretion and MHC class II expression. This effect enhances antigen presentation and biases the immune
response toward a TH1 profile. Live vaccines, such as BCG for tuberculosis, inherently produce danger signals and
stimulate TLRs, eliminating the need for additional adjuvants. In contrast, killed vaccines contain natural adjuvants, while
subunit and recombinant vaccines necessitate synthetic adjuvants due to their lack of innate adjuvant components.
Accessing Intracellular Pathways

What is the purpose of New technologies and experiment vaccine approaches are being made to improve
ICOMs? vaccines’ effectiveness in accessing intracellular pathways:
● ISCOMs: Immunostimulatory complexes are micelles of lipid and subunit
antigens that are lipophilic and capable of penetrating and fusing with the
cell membrane to insert gene sequences in the cell.
○ They also use viruslike particles (VLPs) to add further structure. Both
lipid and VLPs are used in the malaria vaccine.
How are vector ● Vector vaccines use living viruses that have been genetically modified to be
vaccines improved to safe and contains gene sequences for particularpathogenswhich can be
access intracellular expressed intracellularly without live viral replication of the pathogen.
pathways? ○ For example, canarypox is genetically modified to be safe and
contains HIV genes which can be expressed without HIV replication.
How can DNA ● DNA vaccines, if sufficient DNA is administered, can allow cells to express
vaccines be
proteins intracellularly when the genes are injected into cells and tissues.
improved?
How are modern ● Modern adjuvants like MPLs are used to agonize TLRs in cases where
adjuvants used? vaccines do not provide enough stimulation of the innate immune system.
How are conjugate ● Conjugate vaccines are used in cases where vaccines respond poorly with
vaccines used? polysaccharide antigens.
Vaccine Schedules
What determines The scheduling takes into account the clinical implications of each type of infection,
vaccine scheduling?
the person it is being administered to and the geographical location.
For example:
● Rubella vaccines are necessary to prevent intrauterine infections and
Give examples of deformities so it would not be administered to infants.
factors affecting ● Haemophilus is an organism that damages infants so a vaccine against this
vaccine scheduling. would be more suitable.
● HPV vaccines prevent sexual transmission of HPV strains which can cause
cervical cancer do these vaccines are given at puberty.
● Measles affect infants in the developing world whereas it affects school-aged
children in developed world so the vaccines are given at those times.
Immunostimulatory complexes (ISCOMs), composed of lipid and subunit antigens, merge with cell membranes to
insert gene sequences. Virus-like particles (VLPs) provide structural support for ISCOMs, enhancing their
effectiveness, particularly in malaria vaccine development. Vector vaccines use genetically modified living viruses
like canarypox to express specific pathogenic antigens intracellularly without live viral replication. Additionally, DNA
vaccines, if administered in adequate quantities, enable cells to express proteins intracellularly upon injection into
cells and tissues.
Chapter 26: Hypersensitivity Reactions
What are Hypersensitivity reactions are excessive or inappropriate immune responses to

hypersensitivity antigens that cause damage.
reactions? These antigens can be:
1. Infectious antigens
How do infectious
Overzealous/Excessive immune responses to infectious agents and contribute to the
antigens cause
infection, thus causing a type of hypersensitivity disease.
hypersensitivity?
● In the case of infectious antigens, not every antigen can elicit an immune
What is the caveat of
response. However, when they do, the resulting damage can be worse than
infectious antigens?
How bad are the that of the infection itself.
hypersensitivity
○ For example, The common cold elicits a strong immune response but
reactions?
does not lead to hypersensitivity. Influenza can cause
hypersensitivity through an exaggerated immune response where a
Give an example of cytokine storm (high levels of cytokine) is secreted leading to
hypersensitive leukocytes homing to the lungs. The cytokines also cause vascular
reactions caused by changes which result in hypotension and coagulation. If influenza is
infectious antigens. severe, inflammatory cytokines can circulate and negatively affect
remote body parts like the brain (similar to septic shock).
Give an example of an ● Not every infectious agent capable of causing hypersensitivity does so.
infectious antigen with
the possibility of not ○ For example, HBV infections or streptococci infections can result in
causing hypersensitivity in some cases and sometimes they do not. If they
hypersensitivity. cause hypersensitivity it leads to chronic hepatitis and immune
complex disease.
● The overzealous response depends on the immune response genes and the
What determines the infecting dose of the virus.
overzealous immune
response?
Hypersensitivity reactions involve excessive or inappropriate immune responses to antigens, leading to damage.
These antigens can include infectious agents, and overzealous immune responses to these agents may contribute
to hypersensitivity diseases. Not all infectious antigens elicit immune responses, but when they do, the resulting
damage can surpass that caused by the infection itself. For instance, the common cold typically prompts a strong
immune response without leading to hypersensitivity. In contrast, severe influenza can induce hypersensitivity
through an exaggerated immune response, causing a cytokine storm and vascular changes that lead to hypotension
and coagulation. The occurrence of hypersensitivity in response to infectious agents, such as HBV or streptococci,
depends on individual immune response genes and the infecting dose of the virus.
How do environmental 2. Environmental Substances

substances cause Immune responses to innocuous (harmless) environmental antigens can lead to
hypersensitvity hypersensitivities resulting in allergies (hay fever -harmless grass pollen triggers an
reactions? immune response but the immune response is what is causing the harm).
● The environmental substances must gain access to the immune system like in
How do they trigger an the case of dust.
immune response? ○ Dust enters accesses the immune system through the lower respiratory
Give an example. tract when inhaled and mimics the effects of a parasite which triggers
from an IgE dominant response (resulting in immediate hypersensitivity
as allergies like asthma or rhinitis) or an IgG dominant response
(resulting in hypersensitivities like farmer’s lung).
● Small molecular substances can diffuse into the skin and act as haptens which
How do small
trigger delayed hypersensitivity.
molecules trigger an
immune response? ○ For example, the nickel material can cause contact dermatitis.
Give an example
● Injected contact or oral drugs can elicit hypersensitivities mediated by IgE, IgG
or T cells.
What are common ○ These are common hypersensitivities.
hypersensitivities and ○ These hypersensitivities are called idiosyncratic adverse drug reactions.
how do they cause an They can be life-threatening reactions from the smallest doses of drugs.
immune response?
● Allergies are used by clinicians and laypeople to refer to hypersensitive reactions
to exogenous substances, however, texts differentiate it as immediate
Differentiate between hypersensitivity mediated by IgE (a more restrictive definition necessary for
allergies and treatment).
hypersensitivity.
3. Self-antigens
How do self antigens Inappropriate Immune responses to normal host molecules lead to autoimmunity, and
cause when this causes hypersensitivity, it creates autoimmune diseases.
hypersensitivity? ● Some degree of immune response to self-antigens is normal and present in
most people, however, exaggerated/inappropriate responses or a loss of
What is the cause of tolerance to self-antigens, lead to hypersensitive reactions in which autoimmune
this reaction?
diseases can arise.
Hypersensitivity reactions result from exaggerated immune responses and can be triggered by infectious agents,
environmental substances, and self-antigens. Infectious antigens, like those from influenza, can cause overzealous
immune responses, contributing to hypersensitivity diseases. Environmental substances, such as allergens, may
lead to allergies where the immune system reacts excessively to harmless stimuli, resulting in conditions like
asthma. Hypersensitivities can also arise from reactions to injected drugs, potentially causing life-threatening
idiosyncratic adverse drug reactions. Additionally, inappropriate immune responses to normal host molecules can
result in autoimmunity and autoimmune diseases when tolerance to self-antigens is lost.
Who classified the Types of Hypersensitivity Reactions:

hypersensitivity Gell and Combs described a hypersensitivity classification system based on the types of
reactions? immune responses involved and each type of hypersensitivity reaction results in a
What was it based characteristic clinical disease (no matter the antigen involved).
on?
● Hypersensitivity reactions rely on adaptive immunity and antigen priming (previous
What does exposure) to produce the IgE, IgG, and T cell responses characteristic of Type 1,
hypersensitivity Type 2 & 3, and Type 4 hypersensitivity reactions (respectively).
require? ○ This would also mean that hypersensitivity reactions do not occur upon
first exposure to an antigen.
How does it impact
○ The damage of these reactions is caused by different aspects of innate
exposure and
and adaptive immunity
immunity?
1. Type 1
What is Type 1 This is known as Immediate Hypersensitivity or Allergy and is mediated by
hypersensitivity? degranulation of mast cells and eosinophils.
Give some features ● It is triggered within seconds if IgG is performed.

of it. ○ Examples of triggers include schistosomiasis (infectious), house dust
mites (environmental), peanuts (environmental).
What immune ● It is not triggered by autoimmunity.
components ● The adaptive mediator is IgE.
mediate it? ● The innate mediators are mast cells and eosinophils.
Gell and Combs developed a hypersensitivity classification system based on immune responses, resulting in distinct
clinical diseases for each type. Hypersensitivity reactions require prior exposure for adaptive immunity to produce
IgE, IgG, and T cell responses in Type 1, Type 2 & 3, and Type 4 hypersensitivity, respectively. Initial exposure to an
antigen does not induce hypersensitivity reactions. The damage in these reactions involves various aspects of both
innate and adaptive immunity. Type 1 hypersensitivity, known as Immediate Hypersensitivity or Allergy, is
characterized by mast cell and eosinophil degranulation triggered within seconds by IgE. It is not associated with
autoimmunity, and examples of triggers include infectious agents like schistosomiasis and environmental factors like
house dust mites and peanuts.
What is Type 2 2. Type 2

hypersensitivity? This is known as Bound Antigen Hypersensitivity and is caused by IgG binding
with antigens on cell surfaces then interacting with complement or Fc receptors on
macrophages(which results in damage of target cells).
Give some
● It is triggered within seconds if IgG is preformed but the damage from innate
characteristics of it.
mechanisms occurs within hours.
● It is triggered by immune hemolytic anemias.

What is it mediated ● The adaptive mediators are IgG
by?
● The innate mediators are complement and phagocytes.
3. Type 3
This is Immune Complex Hypersensitivity and is caused by antigen-antibody
What is Type 3
hypersensitivity? complexes forming and entering tissues to cause damage or circulating throughout
the body and causing damage elsewhere.
● Both circumstances result in immune complex diseases like

Give some post-streptococcal glomerulonephritis.
● It occurs within hours if IgG is preformed
○ Examples of triggers are post-streptococcal glomerulonephritis
(infectious), farmer’s lung (environmental) and systematic lupus
erythematosus (autoimmunity).
What is it mediated ● The adaptive mediator is IgG

by>
● The innate mediators are complement and neutrophils
Type 2 hypersensitivity, also known as Bound Antigen Hypersensitivity, results from IgG binding to antigens on cell
surfaces, leading to damage of target cells through complement or Fc receptor interactions with macrophages. The
trigger occurs within seconds if preformed IgG is present, with innate damage mechanisms following within hours.
Immune hemolytic anemias are common triggers for this type. In contrast, Type 3 hypersensitivity, called Immune
Complex Hypersensitivity, arises from antigen-antibody complex formation that enters tissues, causing local or
systemic damage. The onset is within hours if preformed IgG is present, with examples including post-streptococcal
glomerulonephritis, farmer's lung, and systemic lupus erythematosus. IgG serves as the adaptive mediator, while
complement and neutrophils are innate mediators.
What is Type 4 4. Type 4

hypersensitivity? This is called Delayed Hypersensitivity and it is mediated by T cells.
It occurs within 2-3 days and is the slowesthypersensitivity.
● It is triggered by hepatitis B virus (infectious), contact dermatitis
Give some (environmental), insulin-dependent diabetes mellitus (autoimmunity),
multiple sclerosis (autoimmunity), rheumatoid arthritis (autoimmunity) and
celiac disease (autoimmunity).
What is it mediated ● The adaptive mediator is T cells.

by?
● The innate mediator is macrophages.
How is hypersensitivity Diagnosis and Treatment

tested? ● Each type of hypersensitivity reaction is diagnosed and treated differently.
How do the tests ● Skin tests might be used to diagnose Type 1 and Type 4 but the skin test
differ?
itself would be based on the disease suspected. Likewise, their treatments
What is the major would differ.
drawback and benefit The Gill and Combs classification may be too simplistic for the overlapping nature of
of the hypersensitivity hypersensitivity reactions but knowledge of the system makes understanding their
classification system? resulting disorders easier, thus improving treatment and diagnosis.
Type 4 hypersensitivity, known as Delayed Hypersensitivity, is mediated by T cells and occurs within 2-3 days,
making it the slowest type of hypersensitivity. Triggers include infectious agents like hepatitis B virus, environmental
factors such as contact dermatitis, and autoimmune conditions like insulin-dependent diabetes mellitus, multiple
sclerosis, rheumatoid arthritis, and celiac disease. T cells serve as adaptive mediators, and macrophages are the
innate mediators. Diagnosis and treatment vary for each type of hypersensitivity, with skin tests commonly used for
Type 1 and Type 4. While the Gell and Coombs classification may have some limitations, understanding it aids in
diagnosing and treating resulting disorders effectively.
Chapter 27:Immediate Hypersensitivity (Type 1): Allergy
What is Atopy? Atopy is an immediate hypersensitivity reaction to environmental antigens mediated by IgE.
Allergy: Involves immediate hypersensitivity mediated by IgE and encompasses conditions

What are allergies?
like anaphylaxis, angioedema, urticaria, rhinitis, asthma, and certain dermatitis types.
● Late-phase reactions with prolonged symptoms may occur when avoiding
environmental antigens proves challenging.
How is it caused? ● Allergens, triggering allergic reactions, enter the body as small particles or
What are allergens? low-molecular-weight substances through inhalation, ingestion, or drug
administration.
Give examples of ○ Inhaled allergens encompass pollens, fungal spores, and house dust mite
their mode of entry.
feces, which often contain enzymes breaking down innate immune barriers.
○ Some insect venoms injected directly into the skin serve as allergens.
Identification and Avoidance:

Treatment in allergy management involves identifying and avoiding allergens, facilitated by
How are allergies thorough history-taking.
treated? ● Seasonal Clues like symptoms occurring in summer may suggest grass pollen
sensitivity, while year-round symptoms indoors may point to house dust mite feces
sensitivity.
Give examples of ● Knowledge of cross-reacting allergens aids allergists in providing effective
some allergies. avoidance strategies.
● Ara h2, a stable peanut protein, causes severe reactions even in cooked foods. Ara
h8, another peanut protein, cross-reacts with birch pollen and other foods, exhibiting
an oral allergy syndrome.
● Cross-reactivity exists between latex and certain foods.
● Involves the β-lactam core of the penicillin molecule, leading to reactions with
related antibiotics like cephalosporins.
● Allergy investigations often require specialist referral, employing methods like
skin-prick or blood testing for detailed analysis.
Degranulating Cells:
What are the
degranulating cells? Mast cells, eosinophils, and basophils are central to allergy, releasing mediators causing
allergic symptoms.
How do mast cells ● Mast cells, expressing IgE receptors, initiate symptoms upon allergen-IgE
perform in allergies? interaction, but other stimuli like complement activation and nervous system signals
can also activate these cells.
Atopy is an immediate hypersensitivity reaction mediated by IgE in response to environmental antigens. Allergy
encompasses various conditions such as anaphylaxis, angioedema, urticaria, rhinitis, asthma, and certain dermatitis
types, all involving immediate hypersensitivity mediated by IgE. Identifying and avoiding allergens are crucial
aspects of allergy management, facilitated by a detailed history, seasonal clues, and understanding cross-reactivity.
The role of degranulating cells, including mast cells, eosinophils, and basophils, is central in releasing mediators that
cause allergic symptoms triggered by allergen-IgE interaction or other stimuli like complement activation and
nervous system signals.
Describe the process

of mast cell
stimulation during
allergies.
Antibody (IgE) in Type I Hypersensitivity:

Type I hypersensitivity requires IgE, produced when B cells, stimulated by IL-4 from TH2
How does IgE perform cells, undergo class switching.
during allergies? ● IgE binds to FcεRI with high affinity, coating mast cells with various IgE against
different antigens.
● Elevated IgE levels are seen in parasitic infections and atopy. Skin-prick testing
or ELISA measures specific IgE levels for allergen investigation.
In Type I Hypersensitivity, the production of IgE antibodies is essential and occurs when B cells, stimulated by IL-4
from TH2 cells, undergo class switching. IgE binds with high affinity to FcεRI, coating mast cells with various IgE
antibodies against different antigens. Elevated IgE levels are observed in conditions such as parasitic infections and
atopy. To investigate allergens, specific IgE levels can be measured through methods like skin-prick testing or
ELISA.
T-Helper Cells:
● TH2 cells, characterized by GATA3 transcription factor, produce IL-4, crucial for
What are TH Cells IgE production in allergy.
roles in allergies?
● TB (TH1 response) and allergy represent opposite poles of adaptive immune
responses, involving a balance of TH1, TH17, and TH2 cells.
How do they respond? ● Tregs prevent extreme polarization, inhibiting both TH1 and TH2 cells,
maintaining balance. Tregs can be induced in allergic individuals, forming the
basis of allergen immunotherapy.
● APCs, making decisions on TH1 or TH2 development, may favor TH2

Which TH response is responses in certain conditions, leading to GATA3 induction and IL-4 production.
preferred and what is ○ APCs decide TH cell direction, maintaining a balance during most
the result? responses, but overpolarization towards TH2 without Tregs may lead to
allergy development
Describe the feedback ● Positive feedback sustains TH2 responses, with IL-4 inhibiting TH1 response
between TH2 and the and enhancing IgE production.
cytokines involved. ○ TH2 cells release other cytokines stimulating eosinophils and inhibiting
TH1 cells, perpetuating the allergic response.
Prevalence and Genetics:

● Allergy affects up to 40% of the developed world's population.
How prevalent are ● Genetic basis: Twin studies show 80% of allergy risk is genetic; specific
allergies? allergies may differ among affected family members.
● Increasing prevalence: Allergy is rising in both developed and developing
worlds.
Filaggrin Gene Variants

● Filaggrin gene polymorphisms established as a cause of allergy.
What genetics factors ● Filaggrin's role in skin barrier maintenance; variants less effective in barrier and
impact allergies? skin moisturization.
● Implication in severe atopic eczema and association with all allergy types.
CD14 Gene Variants:

● Variants in CD14 gene (LPS receptor) interact with LPS levels, affecting allergy
risk.
Type I Hypersensitivity involves an exaggerated immune response, particularly mediated by IgE antibodies, leading
to allergic reactions. Mast cells, eosinophils, and basophils release mediators, causing symptoms upon exposure to
specific antigens. IgE antibodies, crucial for this hypersensitivity, are produced by B cells stimulated by TH2 cells,
coating mast cells with IgE against various antigens. Elevated IgE levels are observed in parasitic infections and
atopic conditions. T-helper cells (TH2) play a key role, producing IL-4 necessary for IgE production, and the balance
between TH1, TH2, and TH17 cells, regulated by Tregs, influences the immune response. Genetic factors, including
filaggrin and CD14 gene variants, contribute to allergy susceptibility. 40% of the developed world has allergies.
How does hygiene Environmental Factors and Allergy:

impact allergy? 1. Hygiene Hypothesis:
● Increasing urbanization linked to rising allergies.
● Growing up on farms, exposure to livestock decreases allergy risk.
● Hygiene hypothesis suggests reduced early-life exposure to microorganisms
contributes to allergy increase.
What complex factors 2. Complex Factors:

impact allergy ● Clinical trials on probiotics and live vaccines show limited allergy prevention
prevalence? benefits.
● Infections with some worms decrease allergy risk despite provoking a TH2
response.
● Allergies rising in areas with common infectious microorganism exposure.
3. Interaction of Genetics and Environment:

What interactions
between genetic and ● Infections can increase or decrease allergy risk based on exposure timing and
environment impact individual genotype.
allergy? ● Air pollution and overabundance of food (leading to obesity) contribute to allergy
rise.
4. Epigenetic Effects
What are epigenetic ● Environmental factors acting in utero or before conception; ongoing research
effects? aims for preventive interventions.
The relationship between environmental factors and allergies is complex. The Hygiene Hypothesis suggests that
urbanization and reduced early-life exposure to microorganisms contribute to rising allergies, while farm exposure
may decrease risk. Trials on probiotics and live vaccines show limited prevention benefits, and certain infections,
despite provoking a TH2 response, may decrease allergy risk. The interplay of genetics and the environment is
crucial, with infections influencing risk based on timing and genotype. Factors like air pollution and obesity also
contribute to the increasing prevalence of allergies, and ongoing research explores preventive interventions through
epigenetic effects, especially those acting before conception.
Chapter 27: Immediate Hypersensitivity (Type 1): Allergy
List 6 mediators of Mediators of Early Phase of Allergy:

early phase allergies. ● Mast Cell Activation: Early allergy phase involves mast cell mediators released
What are their upon IgE-allergen cross-linking.
functions? ● Anaphylaxis: Most severe allergy type; widespread mast cell activation causes
dramatic blood pressure fall.
● Localised Effects: Allergic rhinitis, asthma involve localized blood vessel
changes at allergen entry sites.
● Leukotrienes: Contribute to mucus secretion, bronchoconstriction, and airflow
reduction in asthma.
● Enzyme Release: Degranulating mast cells release enzymes activating
complement and kinins.
● Symptom Persistence: Effects occur within minutes of allergen exposure;
symptoms persist during contin
Treatment of Allergies:
What measure are
taken to treat General Measures:
allergies? ● Tailored treatment based on individual symptoms.
● Identifying and avoiding allergens when possible.
● Challenges in widespread environmental allergens like grass pollen.
Drug Treatments:
● β2-Adrenergic Agonists: Mimic sympathetic nervous system, prevent smooth
List 7 current drug bronchial muscle contraction in asthma.
treatments used in ● Epinephrine: Lifesaving in anaphylaxis; reverses airway obstruction, and
allergies. decreases vascular permeability.
What are they used ● Antihistamines: Block histamine receptors; effective for skin, nose, and
for? mucous membrane allergies.
● Leukotriene Receptor Antagonists: e.g., Montelukast; reduce airway
inflammation in asthma.
● Corticosteroids: Prevent immediate hypersensitivity, late phase, and chronic
allergic inflammation; used topically to avoid side effects.
● Sodium Cromoglycate: Stabilises mast cells, and reduces degranulation.
● Ongoing Developments: Drugs targeting TH2 cytokine pathway, preventing IgE
binding, and reducing allergenicity of environmental allergens.
The early phase of allergy involves mast cell activation and release of mediators upon IgE-allergen cross-linking,
leading to various effects such as anaphylaxis, localized blood vessel changes, and the release of leukotrienes and
enzymes. Symptoms persist during this phase, occurring within minutes of allergen exposure. Treatment
approaches include tailored measures based on individual symptoms, identification and avoidance of allergens
when possible, and drug treatments like β2-adrenergic agonists, epinephrine for anaphylaxis, antihistamines,
leukotriene receptor antagonists, corticosteroids, and sodium cromoglycate. Ongoing developments focus on drugs
targeting the TH2 cytokine pathway, preventing IgE binding, and reducing the allergenicity of environmental
allergens.
Chapter 27: Immediate Hypersensitivity (Type 1): Allergy
What are the effects of Allergen Immunotherapy:

allergy shots? Desensitization (Allergy Shots):
● Targets specific allergens, useful for single-allergen symptoms.
● Risk of anaphylactic attack, requires trained staff and resuscitation equipment.
● Gradual increase in allergen doses to dampen allergic response
Sublingual Immunotherapy:
How is sublingual ● Administered under the tongue for several months.
immunotherapy used? ● Used for hay fever, induces regulatory T cells, reduces allergy symptoms.
Regulatory T Cells in Immunotherapy:

● Large doses induce regulatory T cells that secrete IL-10.
How are Tregs used in
● IL-10 reduces TH2 cell activity, decreases IgE secretion.
immunotherapy?
● Specific IgG secretion increases with regulatory effects.
What influences the Changing Dose and Route:

outcomes of ● Immunologic outcomes influenced by changing dose (in injection
immunotherapy? desensitization) or route of delivery (in sublingual desensitization).
Allergen immunotherapy, including desensitization (allergy shots) and sublingual immunotherapy, targets specific
allergens and is particularly useful for single-allergen symptoms. Allergy shots involve a gradual increase in allergen
doses to dampen the allergic response but carry the risk of anaphylactic attacks, necessitating trained staff and
resuscitation equipment. Sublingual immunotherapy, administered under the tongue for several months, is employed
for hay fever and induces regulatory T cells, reducing allergy symptoms. Large doses of immunotherapy can induce
regulatory T cells that secrete IL-10, diminishing TH2 cell activity and decreasing IgE secretion, while promoting
specific IgG secretion with regulatory effects. Immunologic outcomes are influenced by changing the dose (in
injection desensitization) or the route of delivery (in sublingual desensitization).
Chapter 29: Antibody-Mediated Hypersensitivity (Type2)
What causes Type 2 Antigen-mediated hypersensitivity is caused by IgG and IgM binding to cell surfaces
hypersensitivity? which leads to immune-mediated hemolysis, tissue damage and changes in cell
functions.
What is responsible ● The damage is caused by the antibodies activating the complement or
for the damage? opsonizing/tagging the body's red blood cells.
Self antigens are antigens (biomarkers) found on cell surfaces and are natural to the
body/should not produce an immune response within its respective body whereas
Differentiate between Nonself antigens are foreign and produce an immune response.
self antigens, nonself
antigens, alloantigens ● A self antigen in Person A will be a nonself antigen in Person B, therefore,
and autoantigens. Person A's antigens are allogenic antigens (alloantigens).
○ Alloantigens are normal self-antigens on cell surfaces that are unique
to each individual.
● Autoantigens are antigens recognized as "self" but still trigger an immune
response against it.
What self antigens
belong to red blood Red blood cells possess rhesus and ABO antigens inherited from alleles (mendelian)
cells? at their loci.
Rhesus Blood Group

What categorizes Rh It is based on the presence of an Rh factor gene D (Rh-positive) or absence of Rh factor
positivity or negativity? gene D (Rh-negative) which results in expression or non expression of the conventional
protein antigen D.
● On chromosome 1, the Rh factor genes can be found at loci C, D and E.

Describe the allele ● Having a heterozygous or homozygous D allele results in rhesus positivity.
characteristics of Rh ○ Therefore no anti-D antibodies will be produced (unless there is
positivity and autoimmunity).
negativity ● Having a homozygous null D allele result in rhesus negativity.
○ Therefore an individual will produce anti-D antibodies upon exposure to
D antigens.
Antigen-mediated hypersensitivity involves IgG and IgM binding to cell surfaces, leading to immune-mediated
hemolysis, tissue damage, and alterations in cell functions. The damage occurs when antibodies activate
complement or opsonize, tagging the body's red blood cells. Self antigens, naturally present on cell surfaces and
should not trigger an immune response, can become alloantigens in different individuals, causing an immune
reaction. Alloantigens are unique self-antigens on cell surfaces specific to each person. Autoantigens, recognized as
"self," can still induce an immune response against them. Red blood cells carry rhesus and ABO antigens inherited
from alleles at their loci, and the rhesus blood group is determined by the presence (Rh-positive) or absence
(Rh-negative) of the Rh factor gene D, which contributes to rhesus positivity or negativity based on the individual's D
allele status.
ABO Blood group

What are the A and B A and B antigens are sugars (oligosaccharide molecules, not proteins) similar to that on
antigens? bacteria.
The alleles are inherited codominantly as:
What are the antigen ● A antigen allele -Blood group A
alleles associated with
● B antigen allele -Blood group B
the blood groups?
● Both A and B -Blood group AB
● Null Allele -Blood group O
What are the As expected,

antibodies associated ● Individuals with A antigen produce only Anti-B antibodies
with each blood ● Individuals with B antigen produce only Anti-A antibodies
group? ● Individuals with both A and B antigens will produce neither antibodies
● Individuals with O antigen produce both antibodies.
What are the natural These antibodies are natural antibodies produced by B1 cells against bacteria (IgM)
antibodies?
There is also a nonallelic rbc antigen expressed on RBCs of adults called I which does
What effect does not elicit an immune response (no anti-I produced unless there is autoimmunity).
antibodies again allo- Antibodies produced against alloantigens can lead to type 2 hypersensitivity (like in the
or autoantigens case of blood transfusion or pregnancy). Likewise, antibodies produced against
cause? autoantigens (rhesus factors or I) can type 2 hypersensitivity.
The ABO blood group system involves A and B antigens, which are sugars inherited codominantly. A antigen alleles
result in blood group A, B antigen alleles in blood group B, both A and B alleles in blood group AB, and a null allele
in blood group O. Individuals with A antigen produce Anti-B antibodies, those with B antigen produce Anti-A
antibodies, individuals with both A and B antigens produce neither antibody, and individuals with O antigen produce
both antibodies. These antibodies, natural antibodies produced by B1 cells against bacteria, are IgM antibodies.
Additionally, the I antigen on RBCs does not elicit an immune response, and antibodies against alloantigens or
autoantigens, such as rhesus factors or I, can lead to type 2 hypersensitivity reactions, observed in blood
transfusions or pregnancy.
What are the Anti-RBC Antibodies

anti-RBC antibodies ● IgM against red cell antigens can be natural antibodies against A and B antigens or
against blood autoantibodies against I antigens (causing autoimmune hemolytic anaemia AIHA).
antigens? ○ Recall that natural antibodies, usually IgM, are produced from B1 cells without
antigen exposure and closely related to innate cells.
How does this ● IgG antibodies can be produced against rhesus antigens due to AIHA or allogeneic
occur?
stimulation.
● IgM destroys RBCs via hemolysis where it activates the complement and causes damage
What effect does through the membrane attack complex.
the antibody has on ○ IgG destroys target cells by coating them with IgG which is recognized by Fc
RBCs? receptors on macrophages and leads to phagocytosis of the RBCs.
Alloimmune Hemolysis
Upon exposure to rhesus antigens, IgG antibody is produced and coats the red blood cells.
How does ● Macrophages (in the spleen and liver) use their Fc receptors to detect the coated red cells
alloimmune and destroy them via phagocytosis. This leads to a gradual destruction of RBCs.
hemolysis occur?
This can be seen often in pregnancies (or during labour) where the Rh-negative mother carries
Rh-positive fetus and the fetal cells leaks into her maternal circulation.
Describe the
● Maternal IgG antibodies cross the placenta and bind to fetal red cells which will be
process of
alloimmune destroyed in the foetal spleen and liver.
hemolysis in ● This leads to hemolytic disease of the newborn (positive Coombs test) where the fetus is
pregnancies. born anaemic and each successful pregnancy of an Rh-positive fetus increases the IgG
levels in the mother.
● This disease is treated by exchange transfusion where the fetal red cells are replaced by
a donor Rh-negative cells.The disease can be prevented via Anti-D antibody injections.
Anti-RBC antibodies, mainly IgM, may act as natural antibodies against A and B antigens or as autoantibodies against I
antigens, causing autoimmune hemolytic anemia (AIHA). Natural antibodies, typically IgM, are generated by B1 cells
without prior antigen exposure and are closely associated with innate cells. IgG antibodies can develop against rhesus
antigens due to AIHA or allogeneic stimulation. IgM induces hemolysis by activating the complement and causing damage
through the membrane attack complex, while IgG induces hemolysis by coating target cells, recognized by Fc receptors on
macrophages, leading to phagocytosis of red blood cells. Two types of immune-mediated hemolysis exist: alloimmune
hemolysis, occurring upon exposure to rhesus antigens, and autoimmune hemolysis, which can lead to conditions like
hemolytic disease of the newborn during pregnancies with Rh-incompatible fetuses.
Describe the process Upon exposure to B antigens in an A positive individual or A antigens in an B positive
of a hypersensitive individual: a Hypersensitivity reaction takes place:
reaction to a foreign ● IgM (due to its pentameric nature) quickly and effectively binds to the
blood antigen alloantigens and activates complement cascade/membrane attack complex
(which produces anaphylatoxins C3a and C5a)
● This causes hemolysis of the red blood cells to occur in seconds.
● The anaphylatoxins activate innate immunity and systemic inflammatory
response syndrome (SIDS).
In what situations ● This is seen during blood transfusions where ABO incompatibility occurs.
does this occur? ● If the noncompatible donor cells enter the recipient's body circulation, the
recipient's IgM natural antibodies will hemolyzed the donated cells.
● This occurs between A, B or AB positive individuals.
● O type individuals do not produce this response.
Autoimmune hemolysis
There are different types of autoimmune hemolytic anemia (AIHA) and it can be triggered
by:
What are the methods ● Infections and drugs
by which AIHA can be ● Other autoimmune diseases like systemic lupus erythematosus (SLE).
caused? ● IgM and IgG Autoantibodies (antibodies against self antigens) produced by
malignant daughter B cells against red cell antigens
○ (For example autoantibodies against rhesus antigens are coat the RBCs
which are then removed by the spleen leading to gradual anemia or
against I antigens leading to AIHA by IgM activating complement).
What causes ischemic A symptom of some AIHAs is ischemic damage. This is due to IgM antibodies binding
damage of AIHA? red blood cells below 37° C.
Upon exposure to incompatible ABO antigens, a rapid hypersensitivity reaction occurs in A or B positive individuals,
causing IgM-mediated hemolysis of red blood cells within seconds. This process, observed in ABO-incompatible
blood transfusions, involves the activation of complement cascade and anaphylatoxins, triggering innate immunity
and systemic inflammatory response syndrome (SIRS). O-type individuals do not exhibit this response. Autoimmune
hemolytic anemia (AIHA) can be triggered by infections, drugs, or other autoimmune diseases, leading to the
production of IgM and IgG autoantibodies against red cell antigens. Some AIHAs exhibit symptoms of ischemic
damage due to IgM antibodies binding to red blood cells below 37°C.
What is the solid 1. Type 2 Autoimmune Hypersensitivity Solid Tissue Damage

tissue damage caused This is similar to AIHA in that it can be detected via autoantibodies in blood samples and
by Type 2 treated by removing or blocking the autoantibody.
hypersensitivity?
● Autoantibodies can bind to or attack solid tissue components.
● IgG autoantibodies bind to glycoprotein in the basement membrane of the lung
Describe some and glomeruli which activates the complement and triggers an inflammatory
diseases in which this response.
damage occurs. ○ This is Goodpasture syndrome, determined by the presence of
antibodies for glomerular basement membrane in patient's serum (via
immunofluoescence).
● Antibodies binding to intracellular cement protein desmoglein leads to blistering
skin condition pemphigus.
● IgG antibodies binding to the acetylcholine receptor in skeletal muscle leads to
wide spread weakness in myasthenia gravis.
Type 2 Hypersensitivity affecting Cell Functions:

How does Type 2 Antibodies can bind to other cells and affect their function or stimulate organ functions
hypersensitivity affect without causing much damage.
cell functions? ● In Graves Disease (HLA allele DR3), an anti-TSH receptor autoantibody binds
to the thyroid stimulating hormone receptor and stimulates the thyroid. The
Give examples of this. autoantibody then mimics the effects of the hormone which may lead to:
● Exophthalmos (protruding eyes caused by T cells infiltrating the eye orbit
region and cross reactivity between orbital antigens and thyroid antigens)
● Hyperthyroidism
● Transient natal hyperthyroidism (if the IgG crosses the placenta)
Type 2 autoimmune hypersensitivity involves autoantibodies attacking solid tissue components, causing tissue
damage like in Goodpasture syndrome. The diagnosis is confirmed by detecting antibodies for the glomerular
basement membrane in the patient's serum. Antibodies targeting intracellular cement protein desmoglein lead to the
blistering skin condition pemphigus, while IgG antibodies binding to the acetylcholine receptor in skeletal muscle
result in the widespread weakness observed in myasthenia gravis. Antibodies can impact cell functions without
causing significant damage such as in Graves Disease where the autoantibody mimics the hormone's effects,
potentially leading to symptoms like exophthalmos (protruding eyes caused by T cells infiltrating the eye orbit region
and cross-reactivity between orbital and thyroid antigens), hyperthyroidism, and transient natal hyperthyroidism if the
IgG crosses the placenta.
Chapter 30: Immune Complex Disease (Type 3 Hypersensitivity)
What is the type 3 This is Immune Complex-Mediated Hypersensitivity which is triggered by the
hypersensitivity? persistence of immune complexes within the body, leading to immune-complex diseases.
● Immune complexes are lattices of antigens bound to antibodies and are formed
Describe how it when polyvalent antigens (able to bind to multiple antibodies) elicit an immune
occurs. response and are in slight excess of antibodies.
How do antibodies ● In the beginning stages of an infection, only antigen is present. Then the primary
present affect it? immune response recruits/produces antibodies which form small immune
complexes that circulate.
● Antibody levels rise and larger complexes form.
● Once antigen levels fall after the infection is neutralised, the complexes are no
longer produced.
Type 3 hypersensitivity is the immune-complex mediated hypersensitivity triggered by the infiltration of tissues by
immune complexes, which are lattices of antigens and antibodies. When infection occurs and only antigens are
present, the primary immune response is triggered to stimulate antibodies and form small complexes, then the
antibody levels rise and larger complexes form. Once the infection is neutralized, the complexes are cleared and
antibodies are decreased in production.
The antigens involved in immune complexes are derived from:

1. Infections (Infectious Antigens)
How do Infectious Despite an infection being short lived and controlled due to the body's immune response,
Agents cause some infections can still cause hypersensitivity
hypersensitivity? ● This is due to the infectious antigens forming immune complexes which are not
cleared out and enter bodily tissues.
Give an example of ○ For example, Streptococcal infection
this. ● Some infections aren't very controlled and lead to antigenemia (constant high
antigen levels in the blood) which causes chronic immune complex disease. Like
-Hepatitis B
2. Innocuous Environmental Antigens

What are innocuous
These are antigens from the external environment that are generally harmless but can
environmental
illicit an IgG immune response if they enter bodily tissues due to their small size.
antigens?
Give an example of ● Drugs are environmental antigens as they contain antigens foreign to the body
these agents. (animal serum or synthetic molecules) or haptens which can trigger
What effect may it hypersensitivity.
present? ○ Drugs containing animal serum may also cause serum sickness, which
is antianimal antibodies and immune complexes circulating through the
body due to exposure to animal antiserum.
What are autoantigens 3. Autoantigens

and autoantibodies? Autoantibodies (antibodies targetting self molecules) recognize autoantigens (self
How do they cause proteins marked as nonself by the immune system) causes immune-complex diseases.
hypersensitivity? ○ For example, in the case of systemic lupus erythematosus, DNA
becomes an autoantigen.
Give an example of an ● DNA released from dead cells can elicit an immune response if not cleared.
autoantigen.
Immune complexes involve antigens derived from various sources. Infections, such as Streptococcal infection or
chronic conditions like Hepatitis B, can lead to persistent immune complex formation. Innocuous environmental
antigens, though typically harmless, may trigger an IgG immune response if they penetrate bodily tissues. Drugs,
containing foreign antigens or haptens, can induce hypersensitivity reactions, including serum sickness in response
to animal serum in medications. Autoantigens, marking self-proteins as nonself, contribute to immune complex
diseases when autoantibodies recognize them, as seen in systemic lupus erythematosus where DNA becomes an
autoantigen, potentially causing an immune response if not effectively cleared from the body.
Antibodies and Immune Complexes
What is the antigen Antigen Excess Zone: When an infection begins, antigens are in larger quantity than
excess zone? antibodies.
Then the body produces antibodies which causes the antibody levels in the blood to rise.
Antigen is still in excess so one antigen binds to multiple antibodies which forms small
complexes.
What is the Equivalence Zone: Antibody production continues and the antibody-to-antigen ratio is
equivalence zone? now equal or optimal so large immune complexes are formed (lattices).
Antibody Excess Zone: Immune Complexes are transient (temporary) so bound

What is the antibody antigens in the complex are cleared but innate cells like macrophages. The antigen
excess zone? levels decrease. Once the infection is cleared, antibody levels also decrease.
Persistence: If immune complexes persist and are not cleared, they can constantly
What is immune
circulate throughout the body or enter tissues. They repeatedly trigger complement and
complex persistence?
recruit immune cells/immune responses leading to chronic inflammation and damage.
What does it lead to?
● This leads to immune-complex diseases like SLE, Rheumatoid Arthritis, Serum
Diseases, Post-Streptococcal Glomerulonephritis.
Why should immune Clearance of Immune Complexes:

complexes be In the case of hypersensitivity; macrophages fail to clear the complexes.
cleared? ● (This can be a result of either overproduction of antibodies/exaggerated immune
What cells is response, deficiency in complement/immunodeficiency).
responsible? ● Uncleared immune complexes lead to immune complex diseases once they
circulate within the blood or enter tissues.
In the Antigen Excess Zone, during the early stages of infection, antigens outnumber antibodies, leading to small
complexes forming when one antigen binds to multiple antibodies. In the Equivalence Zone, the antibody-to-antigen
ratio becomes optimal, resulting in the formation of large immune complexes. In Antibody Excess Zone, transient
immune complexes are cleared by innate cells like macrophages, causing a decline in antigen levels. If complexes
persist or failt to clear, chronic inflammation and damage may occur, leading to immune-complex diseases such as
SLEctors like antibody overpro or RA. Complement deficiency can contribute to the development of these diseases.
How does Complement, upon activation by numerous Fc receptors in the immune complex lattice,
complement aid in can activate the classical pathway which causes C3 to break up the immune complex
immune complex and make it soluble
clearance? ● RBCs express the complement receptor 1 which can bind circulating immune
Describe the process. complexes.
● The RBC carry the bound complexes to phagocyte rich areas like the liver or
spleen which triggers phagocytes like macrophages to phagocytose them.
○ This also causes clearance of antigens present in the periphery due to
stimulation of local B cells af the spleen.
If the immune complex pathways are saturated/burdened, there is excessive immune

What is antigenemia? complex production which results in immune complex diseases like antigenemia from
In what ways is it
chronic infections.
caused?
● Lacking complement components or having immunodeficiencies can also cause
this
What damage do Immune complexes cause damage through overstimulating the innate immune system:
uncleared immune ● Activated complement increases vascular permeability and attracts leukocytes
complexes do through ● Innate cells like neutrophils and mast cells are bound to complexes and
the innate immune activated to release proteolytic enzymes that damage blood vessels and cause
system? inflammation.
● Activated platelets bind to the endothelial cells/endothelium and form thrombi.
● Localised damage according to the site of aggregated antigens
● Ischemic damage and occlusion of vessel walls and inflammation of vessel walls
if complexes circulate
● Deposits at joints which cause synovitis
What organs are
affected by immune Organs like the lungs, kidneys, skin and the joints can be severely affected, resulting in
complexes? Farmer's lung and other diseases.
How can type 3 Renal failure is often caused by type 3 hypersensitivity affecting the kidney, especially
hypersensitivity lead since glomerular blood pressure is 4 times higher than the normal systemic circulation
to renal failure? which increases immune complex deposition in walls.
Immune complex lattice activation by Fc receptors triggers the complement classical pathway, making immune
complexes soluble. Red blood cells, equipped with complement receptor 1, bind these complexes and carry them to
phagocyte-rich areas like the liver or spleen, where macrophages undertake their phagocytosis. This process clears
antigens from the periphery and stimulates local B cells in the spleen. Excessive immune complex production,
associated with chronic infections or immunodeficiencies, can lead to immune complex diseases. The resultant
overstimulation of the innate immune system causes increased vascular permeability, leukocyte attraction, and
platelet activation which contributes to ischemic damage, localized damage and inflammation in organs like the
lungs, kidneys, skin, and joints. Renal failure is a frequent outcome, especially when affecting the kidneys with their
elevated glomerular blood pressure.
Why in the kidney and Glomerular and synovial cells both express CR1 so the kidney and the joints are
joints sites of immune subjected to immune complex deposition
complex deposition?
Immune deposition in the kidney causes glomerulonephritis (glomerular inflammation)
What do the kidney which leads to the clinical diagnosis of either:
immune deposits
cause? Nephritis:
● Rapid onset renal failure
● Complement is activated and there is a cellular infiltrate, as neutrophils hone into
What are the clinical the glomeruli causing inflammation which leads to blood and protein leakage into
diagnoses of kidney the urine.
immune deposits? ● This impairs the kidney's ability to excrete metabolites
Differentiate between
Nephrotic syndrome:
both diseases.
● Gradual onset renal failure due to protein leaking into urine.
● Deposition occurs in the basement membrane of glomeruli, causing subtle
damage and protein leakage.
What other diseases There is also postreptococcal glomerulonephritis which is dramatic but short-lived.
cause renal failure? SLE has gradual renal disease.
Goodpasture syndrome and multiple myeloma (damage from light chain) also cause
renal failure.
How are immune ● Indirect immunofluorescence is helpful in this case to identify antibodies
complex antibodies implicated in immune complex diseases and other autoantibodies.
identified?
● For type 3 hypersensitivity, the best case is to avoid antigens but if
What treatments are autoantigens are present, it is not possible.
available for type 3 ○ Corticosteroids are used in such cases.
hypersensitivity? ○ Cyclophosphamide can also be utilized as it inhibits lymphocyte
proliferation.
Immune complex deposition in both glomerular and synovial cells, expressing CR1, affects the kidneys and joints. In
the kidney, immune deposition leads to glomerulonephritis, diagnosed as either nephritis with rapid onset renal
failure or nephrotic syndrome with gradual onset renal failure and protein leakage into urine. Nephritis involves
complement activation, cellular infiltrate, inflammation, and impaired kidney function, while nephrotic syndrome
causes subtle damage in the glomerular basement membrane. Conditions like postreptococcal glomerulonephritis,
SLE, Goodpasture syndrome, and multiple myeloma can result in renal failure. Indirect immunofluorescence aids in
identifying antibodies in immune complex diseases, and corticosteroids or cyclophosphamide may be used in type 3
hypersensitivity cases where antigen avoidance is challenging.
Chapter 31: Delayed Hypersensitivity (Type 4) and Review of Hypersensitivity Reactions
What is delayed Delayed Hypersensitivity:

hypersensitivity? Originally defined as reactions occurring 2 to 3 days post-antigen exposure (e.g.,
tuberculin skin testing), delayed hypersensitivity involves T-helper 1 (TH1) cells driving
What cells are involved
inflammatory responses with macrophages.
in this reaction?
What are the outcomes ● TH17 T cells play a variable role in this process.
of this reaction? ● Multiple sclerosis (MS) and rheumatoid arthritis (RA) are autoimmune diseases
driven by delayed hypersensitivity reactions
Physiological and Pathological Aspects:

What is a characteristic Delayed hypersensitivity can be a physiological response to challenging pathogens
of delayed
and trigger extreme reactions marked by granuloma formation and cell death.
hypersensitivity?
What triggers it? ● It can also respond to innocuous environmental antigens, acting as haptens with
low molecular weight.
Give examples of ● Example, hepatitis B virus, Mycobacterium tuberculosis
diseases.
Environmental and Autoimmune Triggers:
● Delayed hypersensitivity also targets autoantigens, as seen in type 1 diabetes
Describe the effect of
mellitus where TH1 cells respond to pancreatic islet cell antigens, causing
autoimmune and
environmental triggers damage and impairing insulin secretion.
for delayed ○ TH2 and TH17 cells have limited roles in this.
hypersensitivity. ● Nickel in contact dermatitis exemplifies environmental triggers, with contact
dermatitis resulting from exposure to various chemicals like cosmetics and
poison ivy.
Delayed Hypersensitivity and T-Helper 1 Cells:

Delayed hypersensitivity reactions are driven by T-helper 1 (TH1) cells.
What drives delayed ● These reactions begin when tissue macrophages detect danger signals,
hypersensitivity? triggering an inflammatory response.
Describe the process. ● Antigen-loaded dendritic cells move to lymph nodes, presenting antigen to T
cells.
● T-cell clones proliferate and migrate to the inflammation site.
Cytokine Network and TNF:

● T cells and macrophages interact through the cytokine network, with tumor
What roles do cytokines necrosis factor (TNF).
and TNF play in delayed ● TNF, secreted by both macrophages and T cells, contributes significantly to the
hypersensitivity? damage in delayed hypersensitivity reactions.
Delayed hypersensitivity, originally occurring 2 to 3 days post-antigen exposure, involves TH1 cells driving
inflammatory responses, with TH17 cells playing a variable role. Diseases like multiple sclerosis (MS) and
rheumatoid arthritis (RA) are associated with these reactions. Delayed hypersensitivity can respond to pathogens or
innocuous environmental antigens, leading to granuloma formation. In autoimmune conditions like type 1 diabetes
mellitus, TH1 cells respond to pancreatic islet cell antigens. Environmental triggers, such as nickel in contact
dermatitis, contribute to delayed hypersensitivity reactions involving the cytokine network and tumor necrosis factor
(TNF).
WHat are T Cells HLA Alleles and Antigen Presentation:

effect on HLA in ● Due to the requirement for antigen presentation by T cells, delayed
hypersensitivity? hypersensitivity reactions are often linked to specific human leukocyte antigen
(HLA) alleles.
Rheumatoid Arthritis (RA)

What is RA? RA is a chronic condition causing significant joint and tendon swelling and also affecting
the skin, lungs, and eyes as a systemic connective tissue disease.
RA exhibits features of delayed hypersensitivity with persistent TH1 and TH17 reactions
What effects does RA and TNF secretion.
cause? ● Unique autoantibodies, particularly anticyclic citrullinated peptide (CCP)
antibodies recognizing citrullinated proteins, play a crucial diagnostic role.
● The onset of anti-CCP antibodies may precede symptoms by at least 10 years.
Citrullination, is the conversion of arginine to citrulline, and occurs in RA.

What is citrullination
● Citrullination of proteins like fibrin may result from endogenous enzymes
and how is it caused?
activated by inflammation, possibly triggered by factors like smoking or bacterial
infections.
Synovial Inflammation and Immune Cells:

What is synovial In established RA, the synovium is infiltrated by chronic inflammatory cells, including a
inflammation and how mix of TH1 and TH17 cells.
is it caused? ● Cytokines like TNF and IL-17 attract and activate neutrophils, causing synovial
damage.
● Osteoclast activation leads to bone destruction, creating erosions.
● Persistent IL-6 secretion triggers a prolonged acute-phase response.
Delayed hypersensitivity is linked to HLA due to the T cell presentation. RA is a chronic condition mainly impacting
joints (as well as other tissues) and is caused by delayed sensitivity with persistent TH1 and TH17 and TNF
influence/ It uses unique autoantibodies like CCP caused by citrullination of proteins due to inflammation. The
synovium is attacked by chronic inflammatory cells and TNF and IL-17 activate neutrophils and osteoclast to
damage the joint and bone. IL- prolongs the response.
What genetic and Genetic and Environmental Factors:

environmental factors People with RA often have a family history, and the disease is associated with HLA-DR4.
affect RA. ● Associations with specific HLA alleles support the role of T cells in disease
development.
● RA is more common in smokers and those infected with Porphyromonas,
reinforcing the importance of protein citrullination.
Monoclonal antibodies targeting cytokines (TNF, IL-1, IL-6) and B cells are effective
treatments but come with specific risks.
Multiple Sclerosis (MS)

What is MS?
MS is a chronic, disabling neurologic disease characterized by recurring bouts of
inflammation leading to demyelinating plaques in the central nervous system (CNS).
Environmental Factors and Vitamin D:

What factors affect the ● The prevalence of MS is influenced by geographic location, suggesting a link to
prevalence of MS? ultraviolet light exposure (sunlight) and vitamin D synthesis.
● Infections, including Epstein-Barr virus, are implicated as environmental triggers.
● Genetic factors play a smaller role, with a 30% concordance rate in identical
twins.
○ Genes related to vitamin D synthesis are linked to MS, suggesting a
protective role of higher vitamin D levels.
Disease Progression and Neurological Impact:

How does MS In the early stages, acute attacks involve inflammatory lesions with TH1 and TH17 cells
progress? and macrophages in affected nervous tissue.
● This causes reversible, relapsing disability. Myelin loss during inflammation
impairs neuronal impulse conduction, leading to neurologic symptoms.
● Chronic disability later in MS results from irreversible axonal loss, as
demyelinated nerve cells can only remyelinate to a limited extent.
Rheumatoid Arthritis (RA) is influenced by genetic factors, including a familial history and association with HLA-DR4, while
environmental factors like smoking and Porphyromonas infection contribute to disease development. Monoclonal antibodies
targeting cytokines and B cells are effective treatments for RA but carry specific risks. Multiple Sclerosis (MS) is a chronic
neurologic disease causing irreversible neural damgae with recurring inflammatory bouts leading to demyelinating plaques in the
CNS. Environmental factors, such as sunlight exposure and vitamin D synthesis affect MS.
What role do T & B Role of T and B Cells:

cells play in MS? ● T cells are considered initiators of damage in MS, but B cells in the CNS secrete
antibodies against various brain components, including myelin basic protein.
● These antibodies serve as markers for CNS antibody production, aiding in MS
diagnosis.
Treatment of Delayed Hypersensitivity Reactions:

How is delayed In cases of delayed hypersensitivity, avoiding relevant environmental antigens can be
hypersensitivity effective.
treated? ● For example, contact dermatitis may improve by minimizing exposure to
substances like nickel.
● In autoimmune conditions like celiac disease, symptoms can be managed by
adopting diets free of specific triggers, such as gluten, reducing antibody levels.
Anti-Inflammatory Drugs:
How do different types Mechanism of Action:
of anti-inflammatory Anti Inflammatory drugs target mediators released during inflammation, predominantly by
drugs work? innate immune cells.
● Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin inhibit arachidonic
acid metabolism.
● Endogenous corticosteroids, administered at different doses, suppress the
immune response.
Corticosteroids:
These drugs, such as prednisone, exert their effects by influencing gene transcription
Hiow do and direct cell signaling.
corticosteroids work? ● Their primary therapeutic effects are on phagocytes. It may cause
immunosuppression and potential reactivation of infections controlled by
When are they used macrophages.
and what are their ● Corticosteroids at high intravenous doses, are used in conditions like multiple
effects? sclerosis (MS) to reduce macrophage actions but long-term use may cause
toxicity.
● In rheumatoid arthritis (RA), newer biologic drugs that target molecules like TNF,
IL-6, and CD80, as well as B cells.
T cells initiate damage in multiple sclerosis (MS), while CNS-resident B cells produce antibodies against brain
components, aiding in MS diagnosis. Managing delayed hypersensitivity reactions involves avoiding relevant
environmental antigens, such as nickel or gluten, to reduce symptoms. Anti-inflammatory drugs, including NSAIDs
like aspirin and corticosteroids like prednisone, target mediators released during inflammation and suppress the
immune response. High intravenous doses of corticosteroids used in MS may lead to immunosuppression and
infection reactivation. In rheumatoid arthritis, newer biologic drugs targeting molecules like TNF, IL-6, CD80, and B
cells offer alternative therapeutic options.
What role does Interferon (IFN)-β in MS: Recombinant IFN-β delays acute attacks of nervous system
interferon beta play inflammation in MS. It has potential long-term benefits, possibly by preventing chronic
in multiple disability associated with demyelination. The exact mechanism involves reducing T cell
sclerosis? migration across the blood-brain barrier.
What role does Pleomorphism of Cytokines: Cytokines, like IFN-β, exhibit diverse effects on various cell
cytokine play also? types, highlighting the complexity and versatility of their actions.
Immunosuppressive Drugs::
What role does Immunosuppressive drugs play a crucial role in inhibiting the specific immune responses
immunosuppressive underlying autoimmune delayed hypersensitivity, especially when antigen avoidance is not
drugs play in feasible.
hypersensitivity?
● Must balance their therapeutic benefits and potential dangers, notably an
increased susceptibility to infections.
What
● They are mainly used in transplant recipients to prevent rejection but their
considerations must
be taken in their application in autoimmune conditions like multiple sclerosis (MS) is limited
usage? (especially since immunomodulatory drugs have not been tested in MS).:
Immunologically Mediated Drug Reactions:

What are ● These reactions can be either predictable, directly related to a drug's
immune-mediated pharmacologic effects, or idiosyncratic, less predictable, and often
reactions to drugs? immune-mediated.
○ Idiosyncratic Reactions: Some idiosyncratic reactions have an
immunologic basis, involving both the innate and adaptive immune
How does the systems.
immune system ○ These reactions can manifest as any type of hypersensitivity, and
respond to it? antibodies or reactive T cells typically develop after prior exposure to the
drug.
● Diagnosis and Risks: Diagnosing the cause of these reactions is crucial to prevent
life-threatening responses upon repeat exposure.
How are ○ Laboratory tests can provide indirect evidence of immunologic
hypersensitivites hypersensitivity.
diagnosed? ○ Example, Morphine-induced mast cell degranulation, histamine release,
Give an example and the development of the itchy rash urticaria showcase how drugs can
stimulate immune responses.
Recombinant interferon (IFN)-β delays acute attacks in multiple sclerosis (MS) by reducing T cell migration across
the blood-brain barrier, potentially preventing chronic disability. Cytokines like IFN-β exhibit diverse effects,
emphasizing their complex actions on various cell types. Immunosuppressive drugs, crucial in autoimmune
conditions, balance therapeutic benefits with increased infection susceptibility, primarily used in transplant recipients.
Limited application in MS exists, especially compared to immunomodulatory drugs, largely untested in this context.
Immunologically mediated drug reactions, whether predictable or idiosyncratic, highlight the importance of
diagnosing and understanding these responses to prevent life-threatening reactions upon repeat exposure.

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Chapter 1: Introduction to the Immune System

The entire human immune system can be categorized into: Innate

● Phagocytic, nonspecific cells called leukocytes such as

● Complement Cascades and Mediators such as interferons,

Innate Immune responses are triggered within minutes upon identification

Adaptive Immunity consists of:

● Antigen Recognition Molecules which are the diverse repertoire

● Antigen Presenting Cells which are Molecules such as dendritic

Innate and Adaptive Immunity are interconnected:

Other characteristics of lymphocytes:

Diversity and memory are created by:

Both cells started as ancestral genes but innate genes remained

Adaptive immunity is specific, diverse and has immunological memory

Active Immune responses occur in phases:

Types of Immune Responses:

● Intracellular pathogens; (viruses, some bacteria and parasites),

Overview of all Immune Cells:

Antigens are categorized according to tier immune responses:

As well as their origins:

Epitopes are molecular structures found on large antigens that bind to

Both chains are domain/Immunoglobulin folds which are folded repeated

Two fragmented regions that are produced by proteolytic digestion of Igs

Similarly to enzyme-catalyst interactions, antibody-antigen reactions are

Goodness of Fit in this case refers to:

● Antigen binds to well and the excess is washed off

● Patient serum is added and incubate and relevant primary

● The well is washed again to remove irrelevant antibodies but the

● A secondary antibody from an animal conjugated to an enzyme

Describe the Lateral flow test. Lateral Flow Test:

● Urine containing hCG encounters mouse antibody conjugated to

● The urine-antibody mixture encounters a second antibody

● The urine encounters a third antibody specific for mouse

Describe the Immunofluorescence:

● The test is used to detect antigens in cells or tissue sections and

● FITC emits a greenish light when exposed to UV light.

● Direct test: Antibodies (sheep) are added on the biopsy section

Describe Flow Flow Cytometry

● Lymphocytes are incubated with antibodies couple to fluorescent regents

*shaded is light chain

● For the V region to be transcribed, the V region gene segments have to be

● V region of heavy chains consists of: One V segment + One D segment

Describe the process Light Chain Synthesis:

1. Somatic recombination occurs where DNA is rearranged as V-J joins it.

Heavy Chain Synthesis:

1. First Somatic recombination; D-J joined and rearranged DNA is formed.

Describe light chain

Antibody diversity is created by genetic mechanisms, multiple combinations,

● Junctional Diversity: Junctions are formed between gene segments

Describe multiple Multiple Combinations:

Describe somatic Somatic Hypermutation:

What are some Affinity Maturation:

Ig Class Switching: Class switching is the process by which Ig of B cells

B Cells are capable of producing membrane-bound Ig and secreted Ig

● The overall structure of TCR is similar to the membrane-bound

● The 3-dimensional structure of the extracellular portion of the TCR is

Describe alpha chain α TCR Chain:

Describe beta chain β TCR

How do TCRs create T Cell Receptors create diversity using:

CD4 and CD8