KEY POINTS CHAPTER 6

The Normal Immune Response: Cells, Tissues, Receptors,

Mediators, and Overview
The innate immune system uses several families of receptors, notably the
Toll-like receptors, to recognize molecules present in various types of
microbes and produced by damaged cells.
Lymphocytes are the mediators of adaptive immunity and the only cells
that produce specific and diverse receptors for antigens.
T (thymus-derived) lymphocytes express antigen receptors called T cell
receptors (TCRs) that recognize peptide fragments of protein antigens that
are displayed by MHC molecules on the surface of antigen-presenting
cells.
B (bone marrowderived) lymphocytes express membrane bound
antibodies that recognize a wide variety of antigens. B cells are activated
to become plasma cells, which secrete antibodies.
Natural killer (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.
Antigen-presenting cells (APCs) capture microbes and other antigens,
transport them to lymphoid organs, and display them for recognition by
lymphocytes. The most efficient APCs are dendritic cells, which live in
epithelia and most tissues.
The cells of the immune system are organized in tissues, some of which
are the sites of production of mature lymphocytes (the generative
lymphoid organs, the bone marrow and thymus), and others are the sites
of immune responses (the peripheral lymphoid organs, including lymph
nodes, spleen, and mucosal lymphoid tissues).
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, for
example, of the complement system. The reaction of innate immunity is
often manifested as inflammation. Innate immunity, unlike adaptive
immunity, does not have fine antigen specificity or memory.
The defense reactions of adaptive immunity develop slowly, but are more
potent and specialized.
Microbes and other foreign antigens are captured by dendritic cells and
transported to lymph nodes, where the antigens are recognized by nave
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., phagocytosed microbes and
microbes in the cytoplasm of infected cells). Humoral 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+ cytotoxic
T lymphocytes kill cells that express antigens in the cytoplasm that are
seen as foreign (e.g., virus-infected and tumor cells) and can also produce
cytokines.
 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

These are also called allergic reactions, or allergies
They are induced by environmental antigens (allergens) that stimulate
strong TH2 responses and IgE production in genetically susceptible
individuals
IgE coats mast cells by binding to Fc receptors; reexposure to the allergen
leads to cross-linking of the IgE and FcRI, activation of mast cells, and
release of mediators.
The principal mediators are histamine, proteases, and other granule
contents, prostaglandins and leukotrienes, and cytokines.
The 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 phagocytes (macrophages),
which express receptors for the Fc tails of lgG 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 other essential molecules
and cause functional derangements (either inhibition or unregulated
activation) without cell injury.

Mechanisms of T CellMediated 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- activates macrophages to produce substances that cause tissue
damage and promote fibrosis, and IL-17 and other cytokines recruit
leukocytes, thus promoting inflammation.
The classical T cellmediated inflammatory reaction is delayed type
hypersensitivity.
T cellmediated cytotoxicity: CD8+ cytotoxic T lymphocytes (CTLs) specific
for an antigen recognize cells expressing the target antigen and kill these
cells. CD8+ T cells also secrete IFN-.

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 injury
that may expose self antigens and activate APCs and lymphocytes in the
tissues.
Autoimmune diseases are usually chronic and progressive, and the type of
tissue injury is determined by the nature of the dominant immune
response.

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).

Sjgren Syndrome
Sjgren 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 an unknown self antigen expressed in these glands, or immune
reactions against the antigens of a virus that infects the tissues.

Systemic Sclerosis
Systemic sclerosis (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 microvascular disease are commonly present in the
lesions of systemic sclerosis, perhaps causing chronic ischemia, but the
pathogenesis of vascular injury is not known.

Recognition and Rejection of Transplants (Allografts)

The rejection response against solid organ transplants 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 of solid organ grafts:
o Hyperacute rejection. Preformed antidonor 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
caused by T-cell activation and antibodies. The T-cells may secrete
cytokines that induce proliferation of vascular smooth muscle cells,
and the antibodies cause endothelial injury. The vascular lesions
and T-cell reactions cause parenchymal fibrosis.
Treatment of graft rejection relies on immunosuppressive drugs, which
inhibit immune responses against the graft.
Transplantation of hematopoietic stem cells (HSCs) requires careful
matching of donor and recipient and is often complicated by graft-vs-host
diseases (GVHD) and immune deficiency.

Primary (Inherited) Immune Deficiency Diseases

These diseases are caused by inherited mutations in genes involved in
lymphocyte maturation or function, or in innate immunity.
Deficiencies in innate immunity include defects of phagocyte function,
complement, and innate immune receptors.
Some of the common disorders affecting lymphocytes and the adaptive
immune response are:
o X-SCID: failure of T-cell and B-cell maturation; mutation in the
common chain of a cytokine receptor, leading to failure of IL-7
signaling and defective lymphopoiesis
o Autosomal recessive 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 metab
olites during lymphocyte maturation and proliferation
o X-linked agammaglubulinemia (XLA): failure of B-cell maturation,
absence of antibodies; caused by mutations in the BTK gene, which
encodes B-cell 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-linked hyper-IgM syndrome: failure to produce isotype-switched
high-affinity antibodies (IgG, IgA, IgE); mutation in gene encoding
CD40L
o X-linked lymphoproliferative disease (XLP): defect in a signaling
molecule causing defective responses against Epstein-Barr virus
and lymphoproliferation
These diseases present clinically with increased susceptibility to infections
in early life.

Pathogenesis and Course of HIV Infection and AIDS

 Virus entry into cells: requires CD4 and co-receptors, which are receptors
for chemokines; involves binding of viral gp120 and fusion with the cell
mediated by viral gp41 protein; main cellular targets are CD4+ helper T
cells, macrophages, and DCs
Viral replication: provirus genome integrates into host cell DNA; viral gene
expression is triggered 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 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)
Clinical manifestations of AIDS include opportunistic infections, tumors
such as B-cell lymphomas, and CNS
abnormalities.

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;
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 B-cell proliferations (in
which the amyloid deposits consist of immunoglobulin light chains); chronic
inflammatory diseases such as rheumatoid arthritis (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 2-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.