BIOL S302F

Spring 2022

Natural Defense and Immunity

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Animals

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Recognition and Response
• For a pathogen = bacterium, fungus, virus, or other disease-causing agent

• Internal environment of an animal

• A source of nutrients
• A protected setting
• A means of transport to new environments

• Adaptations & evolution → animals developed protections against many pathogens

• Dedicated immune cells in the body fluids and tissues of most animals specifically interact with and
destroy pathogens

• The body’s defenses make up the immune system

• Enables an animal to avoid or limit many infections

• A foreign molecule or cell doesn’t have to be pathogenic to elicit an immune response

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Recognition and Response
• The first lines of defense offered by immune systems help prevent pathogens from gaining entrance to the body

• Outer covering (skin or shell) = blocks entry by many pathogens

• Sealing off the entire body surface is impossible (gas exchange, nutrition, and reproduction)

• Secretions = trap or kill pathogens, guard the body’s entrances and exits (linings of the digestive tract,
airway, and other exchange surfaces)

• If a pathogen breaches barrier defenses and enters the body

• Housed within body fluids and tissues, the invader is no longer an outsider

• Animal’s immune system must detect foreign particles and cells within the body

• Distinguishes nonself from self

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Recognition and Response
• Immune cells produce receptor molecules
→ Bind specifically to molecules from foreign cells or viruses
→ Activate defense responses

• The specific binding of immune receptors to foreign molecules

= molecular recognition

• Central event in identifying nonself molecules, particles,

and cells

• Two types of molecular recognition = two types of immune

defense found among animals

• Innate immunity = common to all animals

• Adaptive immunity = found only in vertebrates.

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Recognition and Response
• In innate immunity

• Barrier defenses (Skin)

• Small set of receptor proteins that bind to molecules or structures that are absent from animal bodies but
common to a group of viruses, bacteria, or other pathogens
• Activates internal defenses = responses to a very broad range of pathogens
• Innate immunity is found in all animals
• As well as in plants = PAMPs and effectors triggered immunity

• In adaptive immunity = Acquired immune response

• Vast arsenal of receptors

• Recognizes a feature typically found only on a particular part of a particular molecule in a particular
pathogen
• High specificity
• Activated after the innate immune response
• Develops more slowly
• Immune response is enhanced by previous exposure to the infecting pathogen
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Innate Immunity
Innate Immunity of Invertebrates

• The great success of insects in terrestrial and freshwater habitats = effectiveness of invertebrate innate immunity

• Insects rely on their exoskeleton as a physical barrier against infection

• Composed largely of the polysaccharide chitin
• Provides an effective barrier defense against most pathogens
• Chitin also lines the insect intestine = blocks infection by food

• Lysozyme = enzyme that breaks down bacterial cell walls

• Protects the insect digestive system

• Internal immune defenses

• Set of recognition proteins, each of which binds to a molecule common to a broad class of pathogens
• Many of these molecules are components of fungal or bacterial cell walls
• Function as “identity tags” for pathogen recognition
• Once bound to a pathogen molecule, a recognition protein triggers an innate immune response

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Innate Immunity
• The major immune cells of insects are called hemocytes

• Some hemocytes ingest and break down microorganisms

• Phagocytosis

• One class of hemocytes produces a defense molecule that helps

entrap large pathogens

• Many other hemocytes release antimicrobial peptides

• Circulate throughout the body of the insect and inactivate or kill
fungi and bacteria by disrupting their plasma membranes

• The innate immune response of insects is specific for particular

classes of pathogens
• Fungus infects an insect → binding of recognition proteins to
fungal cell wall molecules→ activates a transmembrane receptor
called Toll → activates production and secretion of antimicrobial
peptides → specifically kill fungal cells 8
Innate Immunity
• Insects also have specific defenses that protect against infection by viruses

• Many viruses that infect insects have a

genome consisting of a single strand of
RNA
• Virus replicates in the host cell
• RNA strand = template for synthesis of • Because animals do not produce double stranded RNA, its
double-stranded RNA presence can trigger a specific defense against the invading virus 9
Innate Immunity (Mammals)
Innate Immunity of Vertebrates (mammals as research = Human and mouse)

• Barrier Defenses

• The mucous membranes

• Line the digestive, respiratory, urinary, and reproductive tracts
• Produce mucus, a viscous fluid = traps pathogens and other particles
• In the airway, ciliated epithelial cells sweep mucus and any entrapped material upward, helping prevent
infection of the lungs
• Saliva, tears, and mucous provide a washing action that also inhibits colonization by fungi and bacteria
• Create an environment that is hostile to many pathogens
• Lysozyme destroys the cell walls of susceptible
• Pathogens in food or water and those in swallowed mucus must also contend with the acidic
environment of the stomach (pH 2) = kills most of them before they can enter the intestines

• Skin
• Secretions from oil and sweat glands give human skin a pH ranging from 3 to 5
• Acidic enough to prevent the growth of many bacteria
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Innate Immunity (Mammals)
• Cellular Innate Defenses

• (as in insects) Innate immune cells dedicated to detecting, devouring,

and destroying invading pathogens
• Often rely on a Toll-like receptor (TLR)
• Mammalian recognition protein similar to the Toll protein of insects
• TLR recognize pathogens → produce signals → initiate responses tuned
to the invading microorganism
• Each TLR protein binds to fragments of molecules characteristic of a set
of pathogens
TLR3
• On the inner surface of vesicles formed by endocytosis
• Binds to double-stranded RNA (certain viruses)

TLR4 TLR5
• Located on immune cell plasma membranes • Recognizes flagellin, the main protein of bacterial
• Recognizes lipopolysaccharide (surface of many bacteria) flagella
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Innate Immunity (Mammals)
• Cellular Innate Defenses

• The two main types of phagocytic cells in the mammalian body

• Neutrophils: circulate in the blood, attracted by signals from infected tissues and then engulf and
destroy the infecting pathogens

• Macrophages (“big eaters”): are larger phagocytic cells, some migrate throughout the body, others
reside permanently in organs and tissues where they are likely to encounter pathogens
• Some are located in the spleen, where pathogens in the blood are often trapped

• Two other types of cells have roles in innate defense

• Dendritic cells: mainly populate tissues, such as skin, that contact the environment, stimulate adaptive
immunity against pathogens that they encounter and engulf

• Eosinophils: often found in tissues underlying an epithelium, important in defending against

multicellular invaders, such as parasitic worms (discharge destructive enzymes)
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Innate Immunity (Mammals)
• Cellular Innate Defenses

• Cellular innate defenses in vertebrates also involve natural killer cells

• Circulate through the body

• Detect the abnormal array of surface proteins characteristic of some virus-infected and cancerous cells
• Do not engulf stricken cells
• Release chemicals that lead to cell death, inhibiting further spread of the virus or cancer

• Many cellular innate defenses in vertebrates involve the lymphatic system

• Network that distributes the fluid called lymph throughout the body

• Some macrophages reside in lymph nodes → engulf pathogens that have entered the lymph from the
interstitial fluid

• Dendritic cells reside outside the lymphatic system but migrate to the lymph nodes after interacting with
pathogens
• Within the lymph nodes, dendritic cells interact with other immune cells, stimulating adaptive immunity
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Innate Immunity (Mammals)
Lymphatic system

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Innate Immunity (Mammals)
• Antimicrobial Peptides and Proteins

• Pathogen recognition triggers the production and release of a variety of peptides and proteins
• Attack pathogens or impede their reproduction
• (as in insects) Some function as antimicrobial peptides = damaging broad groups of pathogens by disrupting
membrane integrity.
• Others are unique to vertebrate immune systems

• Interferons are proteins that provide innate defense by interfering with viral infections
• Virus-infected body cells secrete interferon proteins that induce nearby uninfected cells to produce
substances that inhibit viral replication
• Limit the cell-to-cell spread
• Some white blood cells secrete a different type of interferon that helps activate macrophages

• The infection-fighting complement system consists of roughly 30 proteins in blood plasma

• Circulate in an inactive state and are activated by substances on the surface of many pathogens
• Activation = cascade of biochemical reactions that can lead to lysis of invading cells
• Also functions in the inflammatory response
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Innate Immunity (Mammals)
• Inflammatory Response

• When a splinter lodges under your skin, → surrounding area becomes swollen and warm to the touch
• Local inflammatory response = set of events triggered by signaling molecules released upon injury or infection

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Innate Immunity (Mammals)
• Inflammatory Response

• Activated macrophages discharge cytokines

• Signaling molecules that recruit neutrophils to the site of injury or infection

• Mast cells (immune cells in connective tissue) release the signaling molecule histamine at sites of damage
• Histamine triggers nearby blood vessels to dilate and become more permeable
• Increase in local blood supply (redness and increased skin temperature)

• Cycles of signaling and response transform the site of injury and infection
• Activated complement proteins promote further release of histamine → attracting more phagocytic cells
• Enhanced blood flow to the site helps deliver antimicrobial peptides

• The result is an accumulation of pus = fluid rich in white blood cells, dead pathogens, and debris from damaged
tissue

• Cells in injured or infected tissue often secrete molecules that stimulate the release of additional neutrophils
from the bone marrow
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Innate Immunity (Mammals)
• Inflammatory Response

• A minor injury or infection = local inflammatory response

• More extensive tissue damage or infection may lead to a response that is systemic (throughout the body)

• In the case of a severe infection, such as meningitis or appendicitis

• Number of white blood cells in the bloodstream may increase several-fold within only a few hours
• A systemic inflammatory response sometimes involves fever
• In response to certain pathogens, substances released by activated macrophages cause the body’s
thermostat to reset to a higher temperature
• There is good evidence that fever can be beneficial in fighting certain infections (underlying mechanism is
still a subject of debate)
• One hypothesis = elevated body temperature may enhance phagocytosis and, by speeding up chemical
reactions, accelerate tissue repair

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Innate Immunity (Mammals)
• Inflammatory Response

• Certain bacterial infections can induce an overwhelming systemic inflammatory response

• Leading to a life-threatening condition = septic shock

• Very high fever

• Low blood pressure
• Poor blood flow through capillaries

• Occurs most often in the very old and the very young
• Fatal in one-third of cases
• Contributes to the death of more than 200,000 people each year in the US.

• Chronic inflammation can also threaten human health

• Crohn’s disease and ulcerative colitis

• Unregulated inflammatory response disrupts intestinal function

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Innate Immunity (Mammals)
• Evasion of Innate Immunity by Pathogens

• Adaptations have evolved in some pathogens

• Enable them to avoid destruction by phagocytic cells

• Outer capsule that surrounds certain bacteria interferes with molecular recognition and phagocytosis
• One such bacterium, Streptococcus pneumoniae, is a major cause of pneumonia and meningitis in humans

• Some bacteria are recognized but resist breakdown after being engulfed by a host cell
• Mycobacterium tuberculosis, rather than being destroyed, this bacterium grows and reproduces within host
cells, effectively hidden from the body’s immune defenses
• Tuberculosis, a disease that attacks the lungs and other tissues
• Worldwide, kills more than 1 million people a year

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Adaptive immunity
• Unique to Vertebrates

• The adaptive response relies on T cells and B cells

• Types of white blood cells called lymphocytes
• Originate from stem cells in the bone marrow (like blood
cells)

• Some migrate from the bone marrow to the thymus (organ in

the thoracic cavity above the heart)
• These lymphocytes mature into T cells

• Lymphocytes that remain and mature in the bone marrow

develop as B cells

• Lymphocytes of a third type remain in the blood and become

the natural killer cells (innate immunity)

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Adaptive immunity
• Any substance that elicits a B or T cell response is called an antigen

• Recognition = B cell or T cell binds to an antigen (bacterial or viral protein) via an antigen receptor
• Each antigen receptor binds to just one part of one molecule from a particular pathogen
• Species of bacteria or strain of virus
• Millions of different antigen receptors
• A given lymphocyte = just one variety
• All of the antigen receptors made by a single B or T cell are identical (100,000 antigen receptors)

• Antigens are usually large foreign molecules, either proteins or polysaccharides

• Surface of foreign cells or viruses
• Released into the extracellular fluid (toxins secreted by bacteria)

• Epitope = The small, accessible portion of an antigen that binds to an antigen receptor
• Group of amino acids in a particular protein

• A single antigen = several epitopes

• Each binding a receptor with a different specificity
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Adaptive immunity

• Antigen Recognition by B Cells and Antibodies Each B cell antigen receptor is a Y-shaped protein consisting of
four polypeptide chains: two identical heavy chains and two identical light chains
• Disulfide bridges link the chains together (Figure 47.9).
• Each light chain or heavy chain has a constant (C) region, where amino acid sequences vary little among the
receptors on different B cells.
• The constant region of heavy chains contains a transmembrane region, which anchors the receptor in the cell’s
plasma membrane.
• As shown in Figure 47.9, each light or heavy chain also has a variable (V) region, so named because its amino acid
sequence varies extensively from one B cell to another.
• Together, parts of a heavy-chain V region and a light-chain V region form an asymmetric binding site for an
antigen.
• Therefore, each B cell antigen receptor has two identical antigen-binding sites.
• Binding of a B cell antigen receptor to an antigen is an early step in B cell activation, leading to formation of cells
that secrete a soluble form of the receptor (Figure 47.10a).
• This secreted protein is called an antibody, also known as an immunoglobulin (Ig).
• Antibodies have the same Y-shaped structure as B cell antigen receptors but lack a membrane anchor.
• As you’ll see later, antibodies provide a direct defense against pathogens in body fluids.
• The antigen-binding site of a membrane-bound receptor or antibody has a unique shape that provides a lock- 23
Adaptive immunity
• B or T cell = specificity for a particular epitope
• Respond to any pathogen that produces molecules containing that epitope

• The antigen receptors of B cells and T cells have similar components but encounter antigens in different ways

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Adaptive immunity
• Antigen Recognition by B Cells and Antibodies

• Y-shaped protein
• Four polypeptide chains: two identical heavy chains and
two identical light chains
• Disulfide bridges link the chains together

• Constant (C) region (AA sequences vary little among the

receptors on different B cells)
• C region of heavy chains contains a transmembrane region

• Variable (V) region (AA sequence varies extensively from one B

cell to another)
• V region of heavy-chain and light-chain V region =
asymmetric binding site for an antigen
• B cell antigen receptor has two identical antigen-binding
sites

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Adaptive immunity
• Antigen Recognition by B Cells and Antibodies

• Binding of a B cell antigen receptor to an antigen = early step in B

cell activation
• Formation of cells that secrete a soluble form of the receptor
= antibody / immunoglobulin (Ig)

• Antibodies = same Y-shaped structure but lack a membrane

anchor
• Provide a direct defense against pathogens in body fluids

• The antigen-binding site = unique shape that provides a lock-and-

key fit for a particular epitope
• Involves any noncovalent bonds between an epitope and the
surface of the binding site

• Bind to intact antigens in the blood and lymph

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Adaptive immunity
• Antigen Recognition by T Cells

• Antigen receptor consists of two different polypeptide chains

• α chain and β chain, linked by a disulfide
• Transmembrane region
• At the outer tip of the molecule = variable (V) regions of the α
and β chains
• Form a single antigen-binding site
• The remainder = the constant (C) regions

• Antigen receptors of T cells bind only to fragments of antigens that

are displayed, or presented, on the surface of host cells

• The host protein that displays the antigen fragment on the cell surface = major histocompatibility complex
(MHC) molecule

• Essential for antigen recognition by T cells

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Adaptive immunity
• The display and recognition of protein antigens begin when
• Pathogen infects a cell of the animal host
• Parts of a pathogen are taken in by an immune cell

• Inside the animal cell

• Enzymes cleave each antigen into antigen fragments (smaller
peptides)
• Each antigen fragment binds to an MHC molecule
• Transports the bound peptide to the cell surface
• Antigen presentation

• If the cell displaying an antigen fragment encounters a T cell with the

right specificity
• Antigen receptor on the T cell can bind to both the antigen
fragment and the MHC molecule
• This interaction of an MHC molecule, an antigen fragment, and
an antigen receptor triggers an adaptive immune response

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Adaptive immunity
• B Cell and T Cell Development

• Four major characteristics of adaptive immunity

• Immense repertoire of lymphocytes and receptors enables detection of antigens and pathogens never before
encountered

• Adaptive immunity normally has self-tolerance, the lack of reactivity against an animal’s own molecules and cells

• Cell proliferation triggered by activation greatly increases the number of B and T cells specific for an antigen

• Stronger and more rapid response to an antigen encountered previously = immunological memory

• Receptor diversity and self-tolerance arise as a lymphocyte matures

• Proliferation of cells and the formation of immunological memory occur later, after a mature lymphocyte
encounters and binds to a specific antigen

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Adaptive immunity
• Generation of B Cell and T Cell Diversity

• Each person
• More than 1 million different B cell antigen receptors
• More than 10 million different T cell antigen receptors

• Only about 20,000 protein-coding genes in the human genome → generation by combinations
• Combining variable elements = millions of different receptors from a very small collection of parts

• Example of immunoglobulin (Ig) gene that encodes the light chain of both membrane-bound B cell antigen
receptors and secreted antibodies (immunoglobulins)

• all B and T cell antigen receptor genes undergo very similar transformations
• The capacity to generate diversity is built into the structure of Ig genes

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Adaptive immunity
• Generation of B Cell and T Cell Diversity

• A receptor light chain is encoded by three gene segments

• a variable (V) segment

encode the variable region of the receptor chain
• a joining (J) segment
• a constant (C) segment encodes the constant region

• The light-chain gene contains:

• a single C segment
• 40 different V segments
• 5 different J segments

• Functional gene = one copy of each type of segment

• Combined in 200 different ways (40 V x 5 J x 1 C)

• The number of different heavy-chain combinations is even greater, resulting in even more diversity

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Adaptive immunity
DNA Rearrangements

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Adaptive immunity
• Generation of B Cell and T Cell Diversity

• Early in B cell development, an enzyme complex = recombinase, links one light-chain V gene segment to one J
gene segment
• Eliminates the long stretch of DNA between the segments
• Forming a single exon that is part V and part J
• Recombinase acts randomly
• Heavy chain genes undergo a similar rearrangement

• In any given cell = only one allele of a light-chain gene and one allele of a heavy-chain gene are rearranged
• Rearrangements are permanent
• Passed on to the daughter cells when the lymphocyte divides

• Antigen receptors can be synthesized

• The rearranged genes are transcribed, and the transcripts are processed for translation
• Each pair of randomly rearranged heavy and light chains results in a different antigen-binding site
• Total population of B cells in a human body: number of such combinations = 3.5 x106
• Mutations introduced during VJ recombination add additional variation
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Adaptive immunity
• Origin of Self-Tolerance

• Antigen receptor genes are randomly rearranged

• Some immature lymphocytes produce receptors specific for epitopes on the organism’s own molecules
• If these self-reactive lymphocytes were not eliminated or inactivated → immune system could not
distinguish self from nonself and would attack body proteins, cells, and tissues

• As lymphocytes mature in the bone marrow or thymus

• Antigen receptors are tested for self-reactivity
• Some B and T cells with receptors specific for the body’s own molecules are destroyed by apoptosis
• The remaining self-reactive lymphocytes are typically rendered nonfunctional

• Since the body normally lacks mature lymphocytes that can react against its own components, the immune
system is said to exhibit self-tolerance

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Adaptive immunity
• Proliferation of B Cells and T Cells

• An antigen is presented to a steady stream of lymphocytes in the lymph nodes until a match is made
• Events that activate the lymphocyte bearing the receptor

• Once activated, a B cell or T cell undergoes multiple cell divisions

• Clone, a population of cells that are identical to the original cell

• Some become effector cells = mostly short-lived cells that take effect immediately against the antigen
• B cells: the effector forms are plasma cells, which secrete antibodies
• T cells: the effector forms are helper T cells and cytotoxic T cells

• The remaining cells become memory cells = long-lived cells that can give rise to effector cells if the
same antigen is encountered later in the animal’s life

• The proliferation into a clone of cells occurs in response to a specific antigen and to immune cell signals

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Adaptive immunity

• Clonal selection → encounter with an antigen

selects which lymphocyte will divide
• Cells that have antigen receptors specific
for other antigens do not respond

• When T cells undergo clonal selection, they

generate memory T cells and effector T cells
(cytotoxic T cells and helper T cells)

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Adaptive immunity
• Immunological Memory

• Responsible for the long-term protection that a prior infection provides against many diseases
• Prior exposure to an antigen alters the speed, strength, and duration of the immune response

• The effector cells formed by clones of lymphocytes after an initial exposure to an antigen produce a primary
immune response
• The primary response peaks about 10–17 days after the initial
exposure

• If the same antigen is encountered again later = secondary

immune response = faster (only 2–7 days after exposure), of
greater magnitude, and more prolonged

• These differences between primary and secondary immune

responses apparent in a graph of the concentrations of specific
antibodies in blood over time
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Adaptive immunity
• Immunological Memory

• The secondary immune response relies on the reservoir of T and B memory cells
• Generated upon initial exposure to an antigen

• Cells are long-lived

• Provide the basis for immunological memory, which can span many decades

• If an antigen is encountered again

• Memory cells specific for that antigen enable the rapid formation of clones of thousands of effector cells also
specific for that antigen

• Generating a greatly enhanced immune defense

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Adaptive immunity: Defense mechanisms
• The defenses provided by B and T lymphocytes:

• Humoral immune responses

• Occurs in the blood and lymph (once called body humors, or fluids)
• Antibodies help neutralize or eliminate toxins and pathogens in body fluids

• Cell-mediated immune responses

• Specialized T cells destroy infected host cells

• Both humoral and cellular immunity can include

• a primary immune response
• a secondary immune response (with memory cells)

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Adaptive immunity: Defense mechanisms
• Helper T Cells: Activating Adaptive Immunity

• A type of T cell that activates humoral and cell-mediated immune responses

• Two conditions must be met

• Foreign molecule must be present that can bind specifically to the antigen receptor of the helper T cell
• This antigen must be displayed on the surface of an antigen-presenting cell

• An antigen-presenting cell = dendritic cell, macrophage, or B cell

• Like immune cells, infected cells can display antigens on their surface

• Two classes of MHC molecules

• Most body cells have only the class I MHC molecules
• Antigen-presenting cells have class I and class II MHC molecules

• Class II molecules provide a molecular signature by which an antigen-presenting cell is recognized

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Adaptive immunity: Defense mechanisms
• Helper T Cells: Activating Adaptive Immunity

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Adaptive immunity: Defense mechanisms
• Helper T Cells: Activating Adaptive Immunity

• A helper T cell and the antigen-presenting cell displaying its specific epitope have a complex interaction
• The antigen receptors (helper T cell) bind to the antigen fragment and to the class II MHC molecule
• At the same time, an accessory protein called CD4 on the helper T cell surface binds to the class II MHC
molecule, helping keep the cells joined

• As the two cells interact, signals in the form of cytokines are exchanged
• Cytokines secreted from a dendritic cell act in combination with the antigen to stimulate the helper T cell,
causing it to produce its own set of cytokines

• Antigen presentation by a dendritic cell or macrophage = helper T cell activation = proliferation (clone of
activated cells)

• Antigen presentation by a B cells to already activated helper T cells = B cells activation

• Activated helper T cells also help stimulate cytotoxic T cells

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Adaptive immunity: Defense mechanisms
• B Cells and Antibodies: A Response to Extracellular Pathogens

• Activation of the B cells

• Involves both helper T cells and proteins on the surface of pathogens
• Stimulated by both an antigen and cytokines
• B cell proliferates and differentiates into memory B cells and antibody secreting plasma cells

• Antigen first binds to receptors on the surface of a B cell

• Cell takes in a few foreign molecules by receptor-mediated endocytosis
• The class II MHC protein of the B cell then presents an antigen fragment to a helper T cell
• This direct cell-to-cell contact is usually critical to B cell activation
• Leads to a robust humoral immune response (single activated B cell = thousands of identical plasma cells)
• Plasma cells stop expressing antigen receptor and begin producing and secreting antibodies
• 2,000 antibodies every second for 4/5 days life span, nearly a trillion antibody molecules in total
• Most antigens recognized by B cells contain multiple epitopes

• A single antigen exposure = variety of B cells activation = different plasma cells producing antibodies directed
against different epitopes on the common antigen
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Adaptive immunity: Defense mechanisms
• B Cells and Antibodies: A Response to Extracellular Pathogens

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Adaptive immunity: Defense mechanisms
• Antibody Function

• Do not directly kill pathogens

• By binding to antigens → interfere with pathogen activity or mark pathogens in various ways for inactivation or
destruction
• Neutralization = a process in which antibodies bind to proteins on the
surface of a virus
• The bound antibodies prevent infection of a host cell, thus neutralizing
the virus
• Sometimes bind to toxins released in body fluids, preventing the toxins
from entering body cells

• Opsonization = antibodies that are bound to antigens on bacteria do not

block infection → present a readily recognized structure for macrophages or
neutrophils, thereby promoting phagocytosis
• Each antibody = two antigen-binding sites →can facilitate phagocytosis
by forming aggregates of bacterial cells, viruses …
• Help fine-tune the humoral immune response
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Adaptive immunity: Defense mechanisms
• Antibody Function

• Phagocytosis enables macrophages and dendritic cells to present antigens → stimulate helper T cells →
stimulate B cells → antibodies → contribute to phagocytosis → …

• Positive feedback between innate and adaptive immunity

• Contributes to a coordinated, effective response to infection
• Antibodies sometimes work together with the proteins of the
complement system
• Binding of a complement protein to an antigen-antibody
complex = generation of a membrane attack complex that forms
a pore in the membrane of the cell
• Ions and water rush into the cell, causing it to swell and lyse
• Whether activated as part of innate or adaptive defenses
• This cascade of complement protein activity results in the
lysis of foreign cells and produces factors that promote
inflammation or stimulate phagocytosis
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Adaptive immunity: Defense mechanisms
• Antibody Function

• Part of a mechanism that can bring the death of infected body cells

• When a virus uses a cell’s biosynthetic machinery to produce viral proteins

• Can appear on the cell surface
• If antibodies specific for epitopes on these viral proteins bind to the exposed proteins
• Presence of bound antibody at the cell surface can recruit a natural killer cell
• The natural killer cell then releases proteins that cause the infected cell to undergo apoptosis
• Activities of the innate and adaptive immune systems are once again closely linked

• B cells can express five types, or classes, of immunoglobulin (IgA, IgD, IgE, IgG, and IgM)
• For a given B cell, each class has an identical antigen-binding specificity but a distinct heavy-chain C region
• IgD, is exclusively membrane bound
• The other four classes have soluble forms, such as the antibodies found in blood, tears, saliva, and breast
milk

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Adaptive immunity: Defense mechanisms
• Cytotoxic T Cells: A Response to Infected Host Cells

• In the absence of an immune response

• Pathogens can reproduce in and kill infected cells

• In the cell-mediated immune response

• Cytotoxic T cells use toxic proteins to kill cells infected by viruses or other intracellular pathogens before
pathogens fully mature

• To become active, cytotoxic T cells require signals from helper T cells and interaction with an antigen-presenting
cell
• Fragments of foreign proteins associate with class I MHC molecules → Displayed on the cell surface
→ Recognized by cytotoxic T cells
• Accessory protein that binds to the MHC molecule = CD8 (helps keep the two cells in contact)
• Destruction involves the secretion of proteins that disrupt membrane integrity and trigger cell death
• Deprives the pathogen of a place to multiply
• Exposes cell contents to circulating antibodies

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Adaptive immunity: Defense mechanisms
• Cytotoxic T Cells: A Response to Infected Host Cells

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Summary of the Humoral and Cell-
Mediated Immune Responses

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Immunization
• The protection provided by a second immune response provides the basis for immunization
• The use of antigens artificially introduced into the body to generate an adaptive immune response and
memory cell formation

• In 1796, Edward Jenner:

• Milkmaids who had cowpox : a mild disease usually seen only in cows
• Did not contract smallpox, a far more dangerous disease
• First documented immunization (or vaccination, from the Latin vacca, cow), Jenner used the cowpox virus to
induce adaptive immunity against the closely related smallpox virus

• Today, immunizations are carried out with vaccines (preparations of antigen)

• Obtained from many sources: inactivated bacterial toxins, killed or weakened pathogens, and even genes
encoding microbial proteins
• These agents induce a primary immune response and immunological memory
• An encounter with the pathogen from which the vaccine was derived triggers a rapid and strong secondary
immune response

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Immunization
• Vaccination programs have been successful against many infectious diseases that once killed or incapacitated
large numbers of people

• A worldwide vaccination campaign led to eradication of smallpox in the late 1970s

• In industrialized nations, routine immunization of infants and children has dramatically reduced the incidence of
sometimes devastating diseases, such as polio and measles

• Unfortunately, not all pathogens are easily managed by vaccination

• Some vaccines are not readily available in impoverished areas of the globe

• Misinformation about vaccine safety and disease risk has led to a growing public health problem
• Measles = Side effects are remarkably rare, with fewer than 1/106 children suffering a significant allergic
reaction to the measles vaccine
• The disease remains quite dangerous to this day (200,000 deaths worldwide each year)
• Declines in vaccination rates in UK, Russia, and the US = recent measles outbreaks
• In 2014–2015, a measles outbreak triggered by a visitor to a Disney theme park in Southern
California spread to multiple states and affected people ranging in age from 6 weeks to 70 years

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Active and Passive Immunity
• Active immunity

• The defenses that arise when a pathogen infection or immunization prompts an immune response

• Passive immunity

• When the IgG antibodies in the blood of a pregnant female cross the placenta to her fetus
• Passive = the antibodies in the recipient are produced by another individual
• IgA antibodies in breast milk provide additional passive immunity to the infant’s digestive tract
• Does not involve the recipient’s B and T cells
• Persists only as long as the transferred antibodies last (a few weeks to a few months)

• Artificial passive immunization

• Antibodies from an immune animal are injected into a nonimmune animal
• Humans bitten by venomous snakes are sometimes treated with antivenin
• Serum from sheep or horses that have been immunized against a snake venom
• Antibodies in antivenin can neutralize toxins in the venom before the toxins do massive damage

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Antibodies as Tools
• Antibodies that an animal produces after exposure to an antigen
are the products of many different clones of plasma cells, each
specific for a different epitope

• Antibodies can also be prepared from a single clone of B cells

grown in culture
• The monoclonal antibodies
• Identical and specific for the same epitope on an antigen

• Basis for many recent advances in medical diagnosis and

treatment
• Home pregnancy test kits use monoclonal antibodies to
detect human chorionic gonadotropin (hCG)
• Therapy for a number of human diseases, including certain
cancers

• Single drop of blood to identify every virus that a person has

encountered through infection or vaccination
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Immune Rejection
• Cells from another person can be recognized as foreign and attacked by immune defenses

• Skin transplanted from one person to a genetically nonidentical person

• Look healthy for a week
• Will then be destroyed (rejected) by the recipient’s immune response

• MHC molecules are a primary cause of rejection

• Each of us expresses MHC proteins from more than a dozen different MHC genes
• More than 100 different versions, or alleles, of human MHC genes
• The sets of MHC proteins on cell surfaces differ between any two people (except identical twins)

• Such differences can stimulate an immune response causing rejection

• To minimize rejection of a transplant or graft, surgeons use donor tissue bearing MHC molecules that match
those of the recipient as closely as possible

• In addition, the recipient takes medicines that suppress immune responses

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Blood Groups
• In the case of blood transfusions

• The recipient’s immune system can recognize carbohydrates on the surface of blood cells as foreign
• Triggering an immediate and devastating reaction

• ABO blood groups

• Type A red blood cells = A carbohydrate on their surface

• Type B red blood cells = B carbohydrate on their surface
• Type AB red blood cells = A and B carbohydrates on their surface
• Type O red blood cells = no carbohydrate on their surface

• Frequently exposed to certain bacteria that have epitopes very similar to the carbohydrates on blood cells

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Disruptions in immune system function
• Allergies

• Exaggerated (hypersensitive) responses to certain antigens called

allergens

• Involve antibodies of the IgE class

• Pollen grains that enter the body → antigen-binding sites of these IgE
antibodies

• Inducing release histamine and other inflammatory chemicals

• Acting on a variety of cell types: sneezing, runny nose, teary
eyes, and smooth muscle contractions in the lungs that can
inhibit effective breathing

• Drugs known as antihistamines block receptors for histamine,

diminishing allergy symptoms (and inflammation)

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Disruptions in immune system function
• Allergies

• An acute allergic → life-threatening reaction = anaphylactic shock

• Inflammatory chemicals released from immune cells trigger

constriction of bronchioles and sudden dilation of peripheral
blood vessels
• Causes a precipitous drop in blood pressure
• Death may occur within minutes due to the inability to breathe
and lack of blood flow

• People with severe hypersensitivities often carry an autoinjector

containing the hormone epinephrine

• Rapidly counteracts this allergic response, constricting peripheral

blood vessels, reducing swelling in the throat, and relaxing
muscles in the lungs to help breathing

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Disruptions in immune system function
• Autoimmune disease

• Immune system is active against particular molecules of the body

• In systemic lupus erythematosus

• The immune system generates antibodies against histones and DNA released by the normal breakdown of
body cells
• Cause skin rashes, fever, arthritis, and kidney dysfunction

• Other targets of autoimmunity

• Insulin-producing beta cells of the pancreas (in type 1 diabetes)

• Myelin sheaths that encase many neurons (in multiple sclerosis)

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Disruptions in immune system function
• Autoimmune disease

• Heredity, gender, and environment all influence susceptibility to autoimmune disorders

• Afflict females more often than males

• Nine times as likely as men to suffer from lupus
• Two to three times as likely to develop rheumatoid arthritis (a damaging and painful inflammation of the
cartilage and bone in joints)

• The causes of this sex bias, as well as the rise in autoimmune disease frequency in industrialized countries, are
areas of active research and debate

• An additional focus of current research on autoimmune disorders is the activity of regulatory T cells, nicknamed
Tregs
• Help modulate immune system activity and prevent response to self-antigens

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Disruptions in immune system function
• Exertion, Stress, and the Immune System

• Moderate exercise improves immune system function and significantly reduces susceptibility to the common
cold and other infections of the upper respiratory tract

• In contrast, exercise to the point of exhaustion leads to more frequent infections and more severe symptoms

• Exercise intensity is the critical variable

• Psychological stress has been shown to disrupt immune system regulation

• Altering the interplay of the hormonal, nervous, and immune systems

• Rest is important for immunity: Adults who averaged fewer than 7 hours of sleep got sick three times as often
when exposed to a cold virus as those who averaged at least 8 hours

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Disruptions in immune system function
• Immunodeficiency Diseases

• A disorder in which an immune system response to antigens is defective or absent

• Can lead to frequent and recurrent infections and increased susceptibility to certain cancers
• An inborn immunodeficiency = genetic or developmental defect in the production of immune system cells or of
specific proteins, such as antibodies or the proteins of the complement system
• Innate or adaptive defenses or both may be impaired

• In severe combined immunodeficiency (SCID)

• Functional lymphocytes are rare or absent
• Lacking an adaptive immune response
• Susceptible to infections that can cause death in infancy (pneumonia and meningitis)
• Treatments = bone marrow and stem cell transplantation

• Exposure to chemicals or biological agents → acquired immunodeficiency

• Drugs (autoimmune diseases/transplant rejection) → immunodeficient state.
• Certain cancers also suppress the immune system

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Pathogen adaptation and evolution
• Antigenic Variation

• Immunological memory is a record of the foreign epitopes an animal has encountered

• If the pathogen stop to expressed those epitopes
• Can reinfect or remain in a host without triggering the rapid and robust response that memory cells provide
• Changes in epitope expression are called antigenic variation

• The parasite that causes sleeping sickness (trypanosomiasis)

• Periodically switching at random among 1,000 versions of the protein found over its entire surface

• Antigenic variation is the main reason the influenza, or “flu,” virus remains a major public health problem.
• As it replicates in one human host after another
• Virus undergoes frequent mutations

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Pathogen adaptation and evolution
• Latency

• Some viruses avoid an immune response by infecting cells and then entering a largely inactive state
• Production of most viral proteins and free viruses ceases
• Latent viruses do not trigger an adaptive immune response
• Viral genome persists in the nuclei of infected cells
• as a separate DNA molecule or as a copy integrated into the host genome

• Latency typically persists until conditions arise that are favorable for viral transmission or unfavorable for host
survival
• Trigger the synthesis and release of free viruses that can infect new hosts

• Herpes simplex viruses in human sensory neurons

• The type 1 virus causes most oral herpes infections
• The type 2 virus is responsible for most cases of genital herpes
• Sensory neurons express relatively few MHC I molecules → infected cells are inefficient at presenting
viral antigens to circulating lymphocytes
• Stimuli reactivate the virus to replicate and infect surrounding epithelial tissues
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Pathogen adaptation and evolution
• The human immunodeficiency virus (HIV)

• Pathogen that causes AIDS

• both escapes and attacks the adaptive immune response

• HIV infects helper T cells with high efficiency by binding specifically to the CD4 accessory protein
• HIV also infects some cell types that have low levels of CD4, such as macrophages and brain cells

• Inside cells, the HIV RNA genome is reverse-transcribed

• The product DNA is integrated into the host cell’s genome
• In this form, the viral genome can direct the production of new viruses

• The body responds to HIV with an immune response → some HIV invariably escapes
• One reason = very high mutation rate
• Altered proteins on the surface reduce interaction with antibodies and cytotoxic T cells
• HIV thus evolves within the body

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Pathogen adaptation and evolution
• The human immunodeficiency virus (HIV)

• Latency
• Latent DNA is shielded from the immune system as well as
from antiviral agents

• Over time, an untreated HIV infection not only avoids the adaptive
immune response but also abolishes it

• Loss of helper T cells, impairing both humoral and cell-

mediated immune responses
• The eventual result is acquired immunodeficiency syndrome
(AIDS)
• Impairment in immune responses that leaves the body susceptible to infections and cancers that a
healthy immune system would usually defeat

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Pathogen adaptation and evolution
• Cancer and Immunity

• When adaptive immunity is inactivated

• Frequency of certain cancers increases dramatically
• Risk of developing Kaposi’s sarcoma is 20,000 times greater for untreated AIDS patients than for healthy
people

• Viruses are involved in about 15–20% of all human cancers

• Immune system can recognize viral proteins as foreign
• Can act as a defense against viruses that can cause cancer and against cancer cells that harbor viruses

• A vaccine introduced in 1986 for hepatitis B virus helps prevent liver cancer
• First cancer for which a human vaccine became available

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Pathogen adaptation and evolution
• Cancer and Immunity

• In the 1970s, Harald zur Hausen proposed that human papillomavirus (HPV) causes cervical cancer

• Many scientists were skeptical that cancer could result from infection by HPV
• HPV = most common sexually transmitted pathogen

• > 10 years = Isolated two particular types of HPV from patients with cervical cancer

• 2006 = development of highly effective vaccines against HPV

• Cervical cancer kills more than 4,000 women annually in the United States
• The fifth-most common cause of cancer deaths among women worldwide

• Administering an HPV vaccine, either Gardasil or Cervarix, to young adults greatly reduces their chance of being
infected with the HPV viruses that cause cervical and oral cancers, as well as genital warts

• In 2008, zur Hausen shared the Nobel Prize in Physiology or Medicine for his discovery
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