Summary of chapter 4

Diseases of the immune system

INNATE AND ADAPTIVE IMMUNITY
Defense against microbes consists of two types of reactions. Innate immunity
(also called natural, or native, immunity) is mediated by cells and proteins that are
always present and poised to fight against microbes, being called into action
immediately in response to infection. The innate immune response is able to
prevent and control many infections.
Adaptive immunity (also called acquired, or specific, immunity). Adaptive
immunity is normally silent and responds (or “adapts”) to the presence of
infectious microbes by becoming active, expanding, and generating potent
mechanisms for neutralizing and eliminating the microbes.
There are two types of adaptive immune responses: humoral immunity, mediated
by soluble proteins called antibodies that are produced by B lymphocytes (also
called B cells), and cell-mediated (or cellular) immunity, mediated by T
lymphocytes (also called T cells).
Cells and Tissues of the Immune System
Lymphocytes are the mediators of adaptive immunity and the only cells that
produce specific and diverse receptors for antigens.
• T (thymus-derived) lymphocytes express TCRs that recognize peptide antigens
displayed by MHC molecules on the surface of APCs.
• B (bone marrow–derived) lymphocytes express membrane- bound antibodies
that recognize a wide variety of antigens. B cells are activated to become plasma
cells, which secrete antibodies.
• NK cells kill cells that are infected by some microbes or are stressed and
damaged beyond repair. NK cells express inhibitory receptors that recognize MHC
molecules that are normally expressed on healthy cells, and are thus prevented
from killing normal cells.
• APCs capture microbes and other antigens, transport them to lymphoid organs,
and display them for recognition by lymphocytes. The most efficient APCs are DCs,
which are located in epithelia and most tissues.
• The cells of the immune system are organized in tissues. Some of these tissues
are the sites of mature lymphocyte production (the generative lymphoid organs,
the bone marrow and thymus), while others are the sites of immune responses
(the peripheral lymphoid organs, including lymph nodes, spleen, and mucosal
lymphoid tissues).
Overview of Normal Immune Responses
• The physiologic function of the immune system is defense against infectious
microbes.
• The early reaction to microbes is mediated by the mechanisms of innate
immunity, which are ready to respond to microbes. These mechanisms include
epithelial barriers, phagocytes, NK cells, and plasma proteins (e.g., of the
complement system). The reaction of innate immunity is often manifested as
inflammation.
• The defense reactions of adaptive immunity develop slowly, but are more potent
and specialized.
• Microbes and other foreign antigens are captured by DCs and transported to
lymph nodes, where the antigens are recognized by naive lymphocytes. The
lymphocytes are activated to proliferate and differentiate into effector and
memory cells.
• Cell-mediated immunity is the reaction of T lymphocytes, designed to combat
cell-associated microbes (e.g., phagocytosis microbes and microbes in the
cytoplasm of infected cells). Humeral immunity is mediated by antibodies and is
effective against extracellular microbes (in the circulation and mucosal lumens).
• CD4+ helper T cells help B cells to make antibodies, activate macrophages to
destroy ingested microbes, stimulate recruitment of leukocytes, and regulate all
immune responses to protein antigens. The functions of CD4+ T cells are mediated
by secreted proteins called cytokines.
CD8+ CTLs kill cells that express antigens in the cytoplasm that are seen as foreign
(e.g., virus-infected and tumor cells).
• Antibodies secreted by plasma cells neutralize microbes and block their
infectivity, and promote the phagocytosis and destruction of pathogens.
Antibodies also confer passive immunity to neonates.
Immediate (Type I) Hypersensitivity
• Also called allergic reactions, or allergies
• Induced by environmental antigens (allergens) that stimulate strong TH2
responses and IgE production in genetically susceptible individuals
• IgE coats mast cells by binding to Fcε receptors; re exposure to the allergen
leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of
mediators.
• Principal mediators are histamine, proteases, and other granule contents;
prostaglandins and leukotriene; and cytokines.
• Mediators are responsible for the immediate vascular and smooth muscle
reactions and the late-phase reaction (inflammation).
• The clinical manifestations may be local or systemic, and range from mildly
annoying rhinitis to fatal anaphylaxis.
Pathogenesis of Diseases Caused by Antibodies and Immune Complexes.
• Antibodies can coat (opsonize) cells, with or without complement proteins, and
target these cells for phagocytosis by macrophages, which express receptors for
the Fc tails of IgG molecules and for complement proteins. The result is depletion
of the opsonized cells.
• Antibodies and immune complexes may deposit in tissues or blood vessels, and
elicit an acute inflammatory reaction by activating complement, with release of
breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory
reaction causes tissue injury.
• Antibodies can bind to cell surface receptors or essential molecules, and cause
functional derangements (either inhibition or unregulated activation) without cell
injury.
Mechanisms of T Cell–Mediated Hypersensitivity Reactions.
• Cytokine-mediated inflammation: CD4+ T cells are activated by exposure to a
protein antigen and differentiate into TH1 and TH17 effector cells. Subsequent
exposure to the antigen results in the secretion of cytokines. IFN-γ activates
macrophages to produce substances that cause tissue damage and promote
fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting
inflammation.
• T cell–mediated cytotoxicity: CD8+ CTLs specific for an antigen recognize cells
expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-γ.
Immunologic Tolerance and Autoimmunity
• Tolerance (unresponsiveness) to self- antigens is a fundamental property of the
immune system, and breakdown of tolerance is the basis of autoimmune diseases.
• Central tolerance: Immature lymphocytes that recognize self- antigens in the
central (generative) lymphoid organs are killed by apoptosis; in the B cell lineage,
some of the self-reactive lymphocytes switch to new antigen receptors that are
not self-reactive.
• Peripheral tolerance: Mature lymphocytes that recognize self- antigens in
peripheral tissues become functionally inactive (anergic), or are suppressed by
regulatory T lymphocytes, or die by apoptosis.
• The factors that lead to a failure of self-tolerance and the development of
autoimmunity include (1) inheritance of susceptibility genes that may disrupt
different tolerance pathways and (2) infections and tissue alterations that may
expose self-antigens and activate APCs and lymphocytes in the tissues.
Systemic Lupus Erythematosus
• SLE is a systemic autoimmune disease caused by autoantibodies produced
against numerous self-antigens and the formation of immune complexes.
• The major autoantibodies, and the ones responsible for the formation of
circulating immune complexes, are directed against nuclear antigens. Other
autoantibodies react with erythrocytes, platelets, and various complexes of
phospholipids with proteins.
• Disease manifestations include nephritis, skin lesions and arthritis (caused by the
deposition of immune complexes), and hematologic and neurologic abnormalities.
• The underlying cause of the breakdown in self-tolerance in SLE is unknown; it
may include excess or persistence of nuclear antigens, multiple inherited
susceptibility genes, and environmental triggers (e.g., UV irradiation, which
results in cellular apoptosis and release of nuclear proteins).
Sjögren Syndrome
• Sjögren syndrome is an inflammatory disease that affects primarily the salivary
and lacrimal glands, causing dryness of the mouth and eyes.
• The disease is believed to be caused by an autoimmune T cell reaction against
one or more unknown self- antigens expressed in these glands, or immune
reactions against the antigens of a virus that infects the tissues.
Systemic Sclerosis
• SS (commonly called scleroderma) is characterized by progressive fibrosis
involving the skin, gastrointestinal tract, and other tissues.
• Fibrosis may be the result of activation of fibroblasts by cytokines produced by T
cells, but what triggers T cell responses is unknown.
• Endothelial injury and micro vascular disease are commonly present in the
lesions of SS, causing chronic ischemia, but the pathogenesis of vascular injury is
not known.
Recognition and Rejection of Organ Transplants (Allografts)
• The graft rejection response is initiated mainly by host T cells that recognize the
foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly
(after uptake and presentation by host APCs).
• Types and mechanisms of rejection comprise the following:
 o Hyper acute rejection: Pre-formed anti donor antibodies bind to graft
endothelium immediately after transplantation, leading to thrombosis,
ischemic damage, and rapid graft failure.
o Acute cellular rejection: T cells destroy graft parenchyma (and vessels) by
cytotoxicity and inflammatory reactions.
o Acute humoral rejection: Antibodies damage graft vasculature.
o Chronic rejection: Dominated by arteriosclerosis, this type is probably
caused by T cell reaction and secretion of cytokines that induce proliferation
of vascular smooth muscle cells, associated with parenchymal fibrosis.
Primary (Congenital) Immune Deficiency Diseases
• Caused by mutations in genes involved in lymphocyte maturation or function, or
in innate immunity.
• Some of the common disorders:
o XLA: failure of B cell maturation, absence of antibodies; caused by
mutations in BTK, which encodes a tyrosine kinase required for maturation
signals from the pre-B cell and B cell receptors.
o Common variable immunodeficiency: defects in antibody production; cause
unknown in most cases.
o Selective IgA deficiency: failure of IgA production; cause unknown.
o X-SCID: failure of T cell and B cell maturation; mutation in the common γ
chain of a cytokine receptor, leading to failure of IL-7 signaling and
defective lymphopoiesis.
o Autosomal SCID: failure of T cell development, secondary defect in
antibody responses; approximately 50% of cases caused by mutation in the
gene encoding ADA, leading to accumulation of toxic metabolites during
lymphocyte maturation and proliferation
o X-linked hyper-IgM syndrome: failure to produce isotypes witched high-
affinity antibodies (IgG, IgA, IgE); mutation in gene encoding CD40L.
• Clinical presentation: increased susceptibility to infections in early life
Human Immunodeficiency Virus Life Cycle and the Pathogenesis of AIDS
• Virus entry into cells: requires CD4 and co-receptors, which are receptors for
chemokine; involves binding of viral gp120 and fusion with the cell mediated by
viral gp41 protein; main cellular targets: CD4+ helper T cells, macrophages, DCs.
• Viral replication: integration of provirus genome into host cell DNA; triggering of
viral gene expression by stimuli that activate infected cells (e.g., infectious
microbes, cytokines produced during normal immune responses)
• Progression of infection: acute infection of mucosal T cells and DCs; viremia with
dissemination of virus; latent infection of cells in lymphoid tissue; continuing viral
replication and progressive loss of CD4+ T cells.
• Mechanisms of immune deficiency:
o Loss of CD4+ T cells: T cell death during viral replication and budding
(similar to other cytopathic infections); apoptosis occurring as a result of
chronic stimulation; decreased thymic output; functional defects.
o Defective macrophage and DC functions
o Destruction of architecture of lymphoid tissues (late) Amyloidosis
• Amyloidosis is a disorder characterized by the extracellular deposits of misfolded
proteins that aggregate to form insoluble fibrils.
• The deposition of these proteins may result from excessive production of
proteins that are prone to misfolding and aggregation; mutations that produce
proteins that cannot fold properly and tend to aggregate; or defective or
incomplete proteolytic degradation of extracellular proteins.
• Amyloidosis may be localized or systemic. It is seen in association with a variety
of primary disorders, including monoclonal plasma cell proliferations (in which the
amyloid deposits consist of immunoglobulin light chains); chronic inflammatory
diseases such as RA (deposits of amyloid A protein, derived from an acute-phase
protein produced in inflammation); Alzheimer disease (amyloid B protein); familial
conditions in which the amyloid deposits consist of mutants of normal proteins
(e.g., Transthyretin in familial amyloid polyneuropathies); amyloidosis associated
with dialysis (deposits of β2-microglobulin, whose clearance is defective).
• Amyloid deposits cause tissue injury and impair normal function by causing
pressure on cells and tissues. They do not evoke an inflammatory response.