Immune System

Mr. Mallappa H ShalavadiHSK College of Pharmacy,

Bagalkot

Immunity refers to protection against infectionsImmune system is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment.

Small HISTORY430 B.C: Peloponesian War, Thucydides describes plague – the ones who had recovered from the disease could nurse the sick without getting the disease a second time15th centurry: Chinese and Turks use dried crusts of smallpox as ”vaccine”1798: Edward Jenner – smallpox vaccineNoticed that milkmades that had contracted cowpox did NOT get smallpoxTest on an 8 year old boy, injected cowpox into himFollwed by exposure to smallpoxVaccine was invented (latin vacca means ”cow”)

TYPES

Two types of adaptive immune responses: humoral immunity, mediated by soluble antibody proteins that are produced by B lymphocytes, and cell-mediated (or cellular) immunity, mediated by T lymphocytes

When the immune system is inappropriately triggered or not properly controlled, the same mechanisms that are involved in host defense cause tissue injury and disease.

The reaction of the cells of innate and adaptive immunity may be manifested as inflammation.

Fungi

Pathogens and disease

Viruses

Protozoa

Large parasites

Bacteria

CELLS AND TISSUES OF THE IMMUNE SYSTEM The cells of the immune system consist of

Lymphocytes, which are the mediators of adaptive immunity

Antigen-presenting cells (APCs), which capture and display microbial and other antigens to the lymphocytes.

Various effector cells, which perform the task of eliminating the antigens (typically, microbes), the ultimate "effect" of the immune response.

Lymphocytesare present in the circulation and

in various lymphoid organs.

Although all lymphocytes appear morphologically identical, there are actually several functionally and phenotypically distinct lymphocyte populations.

Lymphocytes develop from precursors in the generative lymphoid organs

T lymphocytes are so called because they mature in the thymus, whereas B lymphocytes mature in the bone marrow.

Each T or B lymphocyte expresses receptors for a single antigen, and the total population of lymphocytes (numbering about 1012 in humans) is capable of recognizing tens or hundreds of millions of antigens.

This enormous diversity of antigen recognition is generated by the somatic rearrangement of antigen receptor genes during lymphocyte maturation, and variations that are introduced during the joining of different gene segments to form antigen receptors.

Thymus-derived, or T, lymphocytes are the effector cells of cellular immunity and provide important stimuli for antibody responses to protein antigens.

T cells constitute 60% to 70% of the lymphocytes in peripheral blood

T cells do not detect free or circulating antigens.

Instead, the vast majority (>95%) of T cells recognize only peptide fragments of protein antigens that are displayed on other cells bound to proteins of the major histocompatibility complex.

TCRs are noncovalently linked to a cluster of five invariant polypeptide chains, the γ, δ, and ε proteins of the CD3 molecular complex and two ζ chains.

The CD3 proteins and ζ chains do not themselves bind antigens; instead, they interact with the constant region of the TCR to transduce intracellular signals after TCR recognition of antigen.

T-Lymphocytes

T cells express a number of other invariant function-associated molecules.

Like CD4 and CD8 are expressed on distinct T-cell subsets and serve as coreceptors for T-cell activation.

During antigen recognition, CD4 molecules on T cells bind to invariant portions of class II MHC molecules on selected APCs.

CD4+ T cells are "helper" T cells because they secrete soluble molecules (cytokines) that help B cells to produce antibodies and also help macrophages to destroy phagocytosed microbes.

The central role of CD4+ helper cells in immunity is highlighted by the severe compromise that results from the destruction of this subset by human immunodeficiency virus (HIV) infection.

CD8+ T cells can also secrete cytokines, but they play a more important role in directly killing virus-infected or tumor cells, and hence are called "cytotoxic" T lymphocytes (CTLs).

Lymphocyte antigen receptors. A, The T-cell receptor (TCR) complex and other molecules involved in T-cell activation. The TCRα and TCRβ chains recognize antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells), and the linked CD3 complex initiates activating signals. CD4 and CD28 are also involved in T-cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) B, The B-cell receptor complex is composed of membrane IgM and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that promotes B-cell activation.

MHC MoleculesThe human MHC, known as the human leukocyte antigen (HLA)

complex, consists of a cluster of genes on chromosome 6. Plays important role in regulation of immunity.First discovered on leukocytes.On the basis of their chemical structure, tissue distribution, and

function, MHC gene products fall into three categories

Class I MHC molecules are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C.

Each of these molecules is a heterodimer, consisting of a polymorphic 44-kD α chain noncovalently associated with a 12-kD nonpolymorphic β2-microglobulin (encoded by a separate gene on chromosome 15).

The extracellular portion of the α chain contains a cleft where foreign peptides bind to MHC molecules for presentation to CD8+ T cells.

In general, class I MHC molecules bind to peptides derived from proteins synthesized within the cell (e.g., viral antigens).

Because class I MHC molecules are present on all nucleated cells, all virus-infected cells can be detected and eliminated by CTLs.

The HLA complex and the structure of HLA molecules. A, The location of genes in the HLA complex. The sizes and distances between genes are not to scale. The class II region also contains genes that encode several proteins involved in antigen processing (not shown). B, Schematic diagrams and crystal structures of class I and class II HLA molecules. LT, leukotriene; TNF, tumor necrosis factor.

Class II MHC molecules are encoded by genes in the HLA-D region, which contains at least three subregions: DP, DQ, and DR.

Class II MHC molecules are heterodimers of noncovalently linked polymorphic α and β subunits

Unlike in class I, the tissue distribution of class II MHC-expressing cells is quite restricted; they are constitutively expressed mainly on APCs (notably, dendritic cells), and macrophages, and B cells.

In general, class II MHC molecules bind to peptides derived from proteins synthesized outside the cell (e.g., those derived from extracellular bacteria). This allows CD4+ T cells to recognize the presence of extracellular pathogens and to orchestrate a protective response.

Class III MHC include some of the complement components (C2, C3, and Bf); genes encoding tumor necrosis factor (TNF) and lymphotoxin (LT, or TNF-β) are also located within the MHC.

Not associated with Ag identification.

B Lymphocytes

Bone marrow-derived, or B, lymphocytes comprise 10% to 20% of the circulating peripheral lymphocyte population.

They are also present in bone marrow and in the follicles of peripheral lymphoid tissues (lymph nodes, spleen, tonsils, and other mucosal tissues).

B cells are the only cell lineage that synthesize antibodies, also called immunoglobulins (Ig).

B cells recognize antigen via monomeric membrane-bound antibody of the immunoglobulin M (IgM) class, associated with signaling molecules to form the B-cell receptor (BCR) complex.

Whereas T cells can recognize only MHC-associated peptides, B cells can recognize and respond to many more chemical structures, including proteins, lipids, polysaccharides, nucleic acids, and small chemicals; furthermore, B cells (and antibodies) recognize native (conformational) forms of these antigens.

B cells express several invariant molecules that are responsible for signal transduction and for activation of the cells --- These molecules include the CD40 receptor, which binds to its ligand expressed on helper T cells, and CD21, which recognizes a complement breakdown product that is frequently deposited on microbes.

After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies, the mediators of humoral immunity.

The antibodies are gamma globulins called immunoglobulins (abbreviated as Ig), Molecular weights between 160,000 and 970,000.They usually constitute about 20 per cent of all the plasma proteins.All the immunoglobulins are composed of combinations of light and heavy polypeptide chains. Most are a combination of two light and two heavy chains.

Digestion With Papain Yields3 Fragments2 identical Fab and 1 FcFab Because Fragment That is Antigen BindingFc Because Found To Crystallize In Cold Storage

Pepsin DigestionF(ab`)2 No Fc Recovery, Digested Entirely

Mercaptoethanol Reduction (Eliminates Disulfide Bonds) And Alkylation Showed

Enzymatic Digestion Of Antibodies

There are five classes, or isotypes, of immunoglobulins

IgGMost abundant immunoglobin 80% of

serum Ig~10mg/mLIgG1,2,3,4 (decreasing serum

concentration)IgG1, IgG3 and IgG4 cross placentaIgG3 Most effective complement activatorIgG1 and IgG3 High affinity for FcR on

phagocytic cells, good for opsonization

Antibody Classes And Biological Activities

IgM5-10% of serum immunoglobulin1.5mg/mLmIgM (also IgD) expressed on B-cells as

BCRPentameric version is secretedFirst Ig of primary immune responseHigh valence Ig (10 theoretical), 5 empiricalMore efficient than IgG in complement

activation

Antibody Classes And Biological Activities

IgA10-15% of serum IgGPredominant Ig in secretions

○ Milk, saliva, tears, mucus5-15 g of IgA released in secretions!!!!Serum mainly monomeric, polymers

possible not common thoughSecretions, as dimer or tetramer+J-chain

polyptetide+secretory component (Poly IgR)

Antibody Classes And Biological Activities

IgA Antibody Transport Across Cell (Transcytosis)

IgEVery low serum concentration, 0.3g/mLParticipate in immediate hypersensitivities

reations. Ex. Asthma, anaphylaxis, hives Binds Mast Cells and Blood Basophils

thru FcR Binding causes degranulation

(Histamine Release)

Antibody Classes And Biological Activities

IgD Expressed on B-cell Surface

IgM and IgD, Expressed on B-cell Surface

We Do Not Know Any Other Biological Effector Activity

Low serum concentrations, ~30g/mL

Antibody Classes And Biological Activities

Cross-Linkage of Bound IgE Antibody With Allergen Causes

Mechanisms of Action of AntibodiesAntibodies act mainly in two ways to protect the body against invading agents:

(1) by direct attack on the invader

(2) by activation of the “complement system” that then has multiple means of its own for destroying the invader.

The antibodies can inactivate the invading agent in one of several ways, as follows:

1) Agglutination, in which multiple large particles with antigens on their surfaces, such as bacteria or red cells, are bound together into a clump

2) Precipitation, in which the molecular complex of soluble antigen (such as tetanus toxin) and antibody becomes so large that it is rendered insoluble and precipitates

3) Neutralization, in which the antibodies cover the toxic sites of the antigenic agent

4) Lysis, in which some potent antibodies are occasionally capable of directly attacking membranes of cellular agents and thereby cause rupture of the agent

Type Number of ag binding

sites

Site of action Functions

IgG 2

•Blood•Tissue fluid•CAN CROSS PLACENTA

•Increase macrophage activity•Antitoxins•Agglutination

IgM 10•Blood•Tissue fluid

Agglutination

IgA 2 or 4

•Secretions (saliva, tears, small intestine, vaginal, prostate, nasal, breast milk)

•Stop bacteria adhering to host cells•Prevents bacteria forming colonies on mucous membranes

IgE 2 Tissues

•Activate mast cells HISTAMINE•Worm response

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Cell-mediated immunity

cell mediated immune responce.swf

Humoral immunity

HIR.swf

Hypersensivity Reactions

Allergies ------ Greek = altered reactivity

1906 – von Pirquet coined term: hypersensitivity

Hypersensitivity reactions – ‘over reaction’ of the immune system to harmless environmental antigens

“ Defined as a state of exaggerated immune response to an antigen”

Immune responses are capable of causing tissue injury and diseases that are called hypersensitivity diseases.

II. Delayed typeReaction slower in onset and develops within 24-48 hrs

and effects are prolongedMediated by cellular response.

Hypersensitivity reactions – originally divided into 2 categories: immediate and delayedI. Immidiate type Reaction occurs immediately within sec/min after Ag

exposer. Mediated by humoral Ab. Further divided 3 types Type 1, 2 & 3.

Mechanisms of Immunologically Mediated Diseases

Type Prototype Disorder Immune Mechanisms Pathologic LesionsImmediate (type I) hypersensitivity

Anaphylaxis, allergies, bronchial asthma

Production of IgE antibody, immediate release of vasoactive amines and other mediators from mast cells; recruitment of inflammatory cells (late-phase reaction)

Vascular dilation, edema, smooth muscle contraction, mucus production, inflammation

Antibody-mediated (type II) hypersensitivity

Autoimmune hemolytic anemia; Goodpasture syndrome

Production of IgG, IgM →binds to antigen on target cell or tissue, phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes

Phagocytosis and lysis of cells; inflammation; in some diseases, functional derangements without cell or tissue injury

Immune complex-mediated (type III) hypersensitivity

Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness; Arthus reaction

Deposition of antigen-antibody complexes →complement activation →recruitment of leukocytes by complement products and Fc receptors →release of enzymes and other toxic molecules

Inflammation, necrotizing vasculitis (fibrinoid necrosis)

T-cell-mediated (type IV) hypersensitivity

Contact dermatitis; multiple sclerosis; type I diabetes; transplant rejection; tuberculosis

Activated T lymphocytes →(i) release of cytokines and macrophage activation; (ii) T-cell-mediated cytotoxicity

Perivascular cellular infiltrates, edema, cell destruction, granuloma formation

Immediate (Type I) Hypersensitivity

Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host.

The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy.

Many allergens are environmental substances that are harmless for most individuals.

Some individuals apparently inherit genes that make them susceptible to allergies.

This susceptibility is manifested by the propensity of these individuals to make strong TH2 responses and, subsequently, IgE antibody against the allergens.

The IgE is central to the activation of the mast cells and release of mediators that are responsible for the clinical and pathologic manifestations of the reaction.

Immediate hypersensitivity may occur as a local reaction (e.g., seasonal rhinitis, or hay fever) or severely debilitating (asthma) or may culminate in a fatal systemic disorder (anaphylaxis).

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Action Mediator

Vasodilation, increased vascular permeability

HistaminePAFLeukotrienes C4, D4, E4

Neutral proteases that activate complement and kininsProstaglandin D2

Smooth muscle spasm Leukotrienes C4, D4, E4

HistamineProstaglandinsPAF

Cellular infiltration Cytokines (e.g., chemokines, TNF)Leukotriene B4

Eosinophil and neutrophil chemotactic factors (not defined biochemically)

IgE mediated hypertsentivity.swf

Antibody-Mediated Diseases (Type II

Hypersensitivity/Cytotoxicity reaction)

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components.

The antigens may be normal molecules intrinsic to cell membranes or extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite).

Blood cells commonly affected here.

Mechanisms of Antibody-Mediated Diseases

Fig----Effector mechanisms of antibody-mediated injury. A, Opsonization of cells by antibodies and complement components, and

ingestion of opsonized cells by phagocytes. B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement

breakdown products. C, Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease, and acetylcholine (ACh) receptor antibodies impair neuromuscular transmission in myasthenia gravis.

Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)

Disease Target AntigenMechanisms of Disease

Manifestations

Autoimmune hemolytic anemiaAutoimmune thrombocytopenic purpura

Erythrocyte membrane proteins (Rh blood group antigens, I antigen)Platelet membrane proteins (gpllb:Illa integrin)

Opsonization and phagocytosis of erythrocytesOpsonization and phagocytosis of platelets

Hemolysis, anemiaBleeding

Pemphigus vulgaris

Proteins in intercellular junctions of epidermal cells (epidermal cadherin)

Antibody-mediated activation of proteases, disruption of intercellular adhesions

Skin vesicles (bullae)

Vasculitis caused by ANCA

Neutrophil granule proteins

Neutrophil degranulation and inflammation

Vasculitis

Goodpasture syndrome

Noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli

Complement- and Fc receptor-mediated inflammation

Nephritis, lung hemorrhage

Acute rheumatic fever

Streptococcal cell wall antigen; antibody cross-reacts with myocardial antigen

Inflammation, macrophage activation

Myocarditis, arthritis

Myasthenia gravis

Acetylcholine receptor Antibody inhibits acetylcholine binding, down-modulates receptors

Muscle weakness, paralysis

Graves disease (hyperthyroidism)

TSH receptor Antibody-mediated stimulation of TSH receptors

Hyperthyroidism

Insulin-resistant diabetes

Insulin receptor Antibody inhibits binding of insulin

Hyperglycemia, ketoacidosis

Pernicious anemia

Intrinsic factor of gastric parietal cells

Neutralization of intrinsic factor, decreased absorption of vitamin B12

Abnormal erythropoiesis, anemia

ANCA, antineutrophil cytoplasmic antibodies; TSH, thyroid-stimulating hormone.

Immune Complex Diseases (Type III Hypersensitivity)

Antigen-antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation.

The antigens in these complexes may be exogenous antigens-microbial proteins, or endogenous antigens-nucleoproteins.

The formation of immune complexes does not equate with hypersensitivity disease; antigen-antibody complexes are produced during many immune responses and are usually phagocytosed, representing a normal mechanism of antigen removal.

It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic.

Pathogenic immune complexes may form in the circulation and subsequently deposit in blood vessels, or the complexes may form at sites where antigen has been planted.

Immune complex-mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs

localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site.

The sequential phases in the induction of systemic immune complex mediate- d diseases (type III hyper- sensitivity).

Systemic Immune Complex Disease The pathogenesis of systemic immune complex disease can be divided into three phases

Local Immune Complex Disease

A model of local immune complex diseases is the Arthus reaction, an area of tissue necrosis resulting from acute immune complex vasculitis.

The reaction is produced experimentally by injecting an antigen into the skin of a previously immunized animal (i.e., preformed antibodies against the antigen are already present in the circulation).

Because of the initial antibody excess, immune complexes are formed as the antigen diffuses into the vascular wall; these are precipitated at the site of injection and trigger the same inflammatory reaction and histologic appearance as in systemic immune complex disease.

Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection, when the injection site develops visible edema with severe hemorrhage, occasionally followed by ulceration.

Disease Antigen Involved Clinicopathologic Manifestations

Systemic lupus erythematosus

Nuclear antigens Nephritis, skin lesions, arthritis, others

Poststreptococcal glomerulonephritis

Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane

Nephritis

Polyarteritis nodosa Hepatitis B virus antigen

Systemic vasculitis

Reactive arthritis Bacterial antigens (Yersinia)

Acute arthritis

Serum sickness Various proteins, such as foreign serum protein (horse anti-thymocyte globulin)

Arthritis, vasculitis, nephritis

Arthus reaction (experimental)

Various foreign proteins

Cutaneous vasculitis

Examples of Immune Complex-Mediated Diseases

T-Cell-Mediated (Type IV) HypersensitivityCell mediated reaction. This group of diseases has received great interest because many of

the new, rationally designed biologic therapies for immune-mediated inflammatory diseases have been developed to target abnormal T-cell reactions.

Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells.

Two types of T-cell reactions are capable of causing tissue injury and disease:

(1) Delayed-type hypersensitivity (DTH), initiated by CD4+ T cells

(2) Direct cell cytotoxicity, mediated by CD8+ T cells.

In DTH, TH1-type CD4+ T cells secrete cytokines, leading to recruitment of other cells, especially macrophages, which are the major effector cells of injury.

In cell-mediated cytotoxicity, cytotoxic CD8+ T cells are responsible for tissue damage.

Delayed-Type Hypersensitivity A classic example of DTH is the tuberculin reaction,

elicited by antigen challenge in an individual already sensitized to the tubercle bacillus by a previous infection.

Between 8 and 12 hours after intracutaneous injection of tuberculin (a protein extract of the tubercle bacillus), a local area of erythema and induration appears, reaching a peak (typically 1-2 cm in diameter) in 24 to 72 hours (hence the adjective, delayed) and thereafter slowly subsiding.

Histologically, the DTH reaction is characterized by perivascular accumulation ("cuffing") of CD4+ helper T cells and macrophages.

Local secretion of cytokines by these mononuclear inflammatory cells leads to increased microvascular permeability, giving rise to dermal edema and fibrin deposition; the latter is the main cause of the tissue induration in these responses.

The tuberculin response is used to screen populations for individuals who have had prior exposure to tuberculosis and therefore have circulating memory T cells specific for mycobacterial proteins.

Notably, immunosuppression or loss of CD4+ T cells (e.g., resulting from HIV infection) may lead to a negative tuberculin response even in the presence of a severe infection.

T-Cell-Mediated Cytotoxicity In this form of T-cell-mediated hypersensitivity, CD8+ CTLs kill

antigen-bearing target cells. As discussed earlier, class I MHC molecules bind to intracellular

peptide antigens and present the peptides to CD8+ T lymphocytes, stimulating the differentiation of these T cells into effector cells called CTLs.

CTLs play a critical role in resistance to virus infections and some tumors.

The principal mechanism of killing by CTLs is dependent on the perforin-granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC-bound peptides).

Perforin binds to the plasma membrane of the target cells and promotes the entry of granzymes, which are proteases that specifically cleave and thereby activate cellular caspases.

These enzymes induce apoptotic death of the target cells. CTLs play an important role in the rejection of solid-organ transplants

and may contribute to many immunologic diseases, such as type 1 diabetes (in which insulin-producing β cells in pancreatic islets are destroyed by an autoimmune T-cell reaction).

Immunological tolerance It is unresponsiveness to an antigen that is induced by

exposure of specific lymphocytes to that antigen. Self-tolerance refers to a lack of immune responsiveness

to one's own tissue antigens. During the generation of billions of antigen receptors in

developing T and B lymphocytes, it is not surprising that receptors are produced that can recognize self-antigens.

Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes.

Several mechanisms work in concert to select against self-reactivity and to thus prevent immune reactions against one's own antigens.

These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance

Central tolerance-----△ This refers to deletion of self-reactive T and B

lymphocytes during their maturation in central lymphoid organs.

△ Many autologous (self) protein antigens are processed and presented by thymic APCs in association with self-MHC.

△ Any developing T cell that expresses a receptor for such a self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells.

Immature B cells that recognize, with high affinity, self-antigens in the bone marrow may also die by apoptosis.

Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and express new receptors that are no longer self-reactive (a process called "receptor editing").

Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery.

There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals

oPeripheral tolerance. o Self-reactive T cells that escape negative selection in the thymus can

potentially wreak havoc unless they are deleted or effectively muzzled.

o Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified:

o Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions.

o Recall that activation of T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on APCs, and a set of second costimulatory signals (e.g., via B7 molecules) provided by the APCs.

o If the second costimulatory signals are not delivered, or if an inhibitory receptor on the T cell is engaged when the cell encounters self-antigen, the T cell becomes anergic and cannot respond to the antigen

o B cells can also become anergic if they encounter antigen in the absence of specific helper T cells

Suppression by regulatory T cells: The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells.

Activation-induced cell death: Another mechanism of peripheral tolerance involves

apoptosis of mature lymphocytes as a result of self-antigen recognition.

T cells that are repeatedly stimulated by antigens in vitro undergo apoptosis. One mechanism of apoptosis is the death receptor Fas (a member of the TNF receptor family) being engaged by its ligand coexpressed on the same cells.

The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on helper T cells.

Autoimmunity Self-tolerance fails, resulting in reactions against one's

own cells and tissues that are called autoimmunity. The diseases caused by autoimmunity are referred to as

autoimmune diseases.

Mechanisms of AutoimmunityThe breakdown of self-tolerance and the development of

autoimmunity are probably related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury, that alter the display and recognition of self-antigens

Genetic Factors in AutoimmunityThere is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseasesExpression of a particular MHC gene variable that can contribute to autoimmunity.

Disease HLA AlleleRelative Risk (approximate %)

Ankylosing spondylitis B27 90-100Postgonococcal arthritis B27 14Acute anterior uveitis B27 15Rheumatoid arthritis DR4 4Autoimmune hepatitis DR3 14Primary Sjögren syndrome DR3 10Type 1 diabetes mellitus DR3 5

Two genetic polymorphisms have recently been shown to be quite strongly associated with certain autoimmune diseases.

One, called PTPN22, encodes a phosphatase, and particular variants are associated with rheumatoid arthritis and several other autoimmune diseases.

Another, called NOD2, encodes an intracellular receptor for microbial peptides, and certain variants or mutants of this gene are present in as many as 25% of patients with Crohn's disease in some populations.

Role of Infections and Tissue Injury A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoimmunity.

Viruses and other microbes, particularly certain bacteria such as streptococci and Klebsiella organisms, may share cross-reacting epitopes with self-antigens, such that responses to the microbial antigen may attack self-tissues.

This phenomenon is called molecular mimicry.

It is the probable cause of a few diseases, the best example being rheumatic heart disease, in which an immune response against streptococci cross-reacts with cardiac antigens.

Local tissue injury for any reason may lead to the release of self-antigens and autoimmune responses

REJECTION OF TRANSPLANTS

The major barrier to transplantation of organs from one individual to another of the same species (called allografts) is immunologic rejection of the transplanted tissue.

Rejection is a complex phenomenon involving both cell- and antibody-mediated hypersensitivity reactions directed against histocompatibility molecules on the foreign graft.

The key to successful transplantation has been the development of therapies that prevent or minimize rejection.

MechanismRejection of allografts is a response to MHC molecules,

which are so polymorphic that no two individuals in an outbred population are likely to express exactly the same set of MHC molecules (except, of course, for identical twins).

There are two main mechanisms by which the host immune system recognizes and responds to the MHC molecules on the graft.

Direct recognition

Indirect recognition

Host T cells directly recognize the allogeneic (foreign) MHC molecules that are expressed on graft cells.

Direct recognition of foreign MHC seems to violate the rule of MHC restriction

It is suggested that allogeneic MHC molecules (with any bound peptides) structurally mimic self-MHC and foreign peptide, and so direct recognition of the allogeneic MHC is essentially an immunologic cross-reaction.

Because DCs in the graft express high levels of MHC.

Host CD4+ helper T cells are triggered into proliferation and cytokine production by recognition of donor class II MHC (HLA-D) molecules and drive the DTH response.

CD8+ T cells recognize class I MHC (HLA-A, -B) and differentiate into CTLs, which kill the cells in the graft.

Direct recognition

Indirect recognition Host CD4+ T cells recognize donor MHC molecules after

these molecules are picked up, processed, and presented by the host's own APCs.

This is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens.

This form of recognition mainly activates DTH pathways; CTLs that develop by indirect recognition cannot directly recognize and kill graft cells.

The indirect pathway is also involved in the production of antibodies against graft alloantigens; if these antigens are proteins, they are picked up by host B cells, and peptides are presented to helper T cells, which then stimulate antibody responses.