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  • Effector Functions of T Lymphocytes Body_ID: HC005019 One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes. Some of the progeny of the expanded pool of T cells differentiate into effector cells that can secrete different sets of cytokines and thus perform different functions. The best defined subsets of CD4+ helper cells are the TH1 and TH2 subsets. TH1 cells produce the cytokine IFN-γ, which activates macrophages and stimulates B cells to produce antibodies that activate complement and coat microbes for phagocytosis. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus and expel microbes. A third subset, called TH17, has been described recently that produces the cytokine IL-17, which promotes inflammation, and is believed to play an important role in some T cell-mediated inflammatory disorders. These effector cells migrate to sites of infection and accompanying tissue damage. When the differentiated effectors again encounter cell-associated microbes, they are activated to perform the functions that are responsible for elimination of the microbes. The key mediators of the functions of helper T cells are the surface molecule called CD40 ligand (CD40L), which binds to its receptor, CD40, on B cells and macrophages, and various cytokines. Differentiated CD4+ effector T cells of the TH1 subset recognize microbial peptides on macrophages that have ingested the microbes. The T cells express CD40L, which engages CD40 on the macrophages, and the T cells secrete the cytokine, IFN-γ, which is a potent macrophage activator. The combination of CD40- and IFN-γ-mediated activation results in the induction of potent microbicidal substances in the macrophages, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbes. TH2 cells elicit cellular defense reactions that are dominated by eosinophils and not macrophages. As we discuss below, CD4+ helper T cells also stimulate B-cell responses by CD40L and cytokines. Body_ID: P005043 Activated CD8+ lymphocytes differentiate into CTLs that kill cells harboring microbes in the cytoplasm. These microbes may be viruses that infect many cell types, or bacteria that are ingested by macrophages but have learned to escape from phagocytic vesicles into the cytoplasm (where they are inaccessible to the killing machinery of phagocytes, which is largely confined to vesicles). By destroying the infected cells, CTLs eliminate the reservoirs of infection.
  • Figure 5-16 Recognition and rejection of organ allografts. In the direct pathway, donor class I and class II MHC antigens on antigen-presenting cells (APCs) in the graft (along with costimulators, not shown) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively. CD4+ cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed-hypersensitivity reaction. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells. In the indirect pathway, graft antigens are displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed-hypersensitivity reaction and stimulate B lymphocytes to produce antibodies.
  • Immunology

    1. 1. Mr. Mallappa H Shalavadi HSK College of Pharmacy, Bagalkot
    2. 2. Immunity refers to protection against infections Immune system is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment. Small HISTORY 430 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 time 15th centurry: Chinese and Turks use dried crusts of smallpox as ”vaccine” 1798: Edward Jenner – smallpox vaccine Noticed that milkmades that had contracted cowpox did NOT get smallpox Test on an 8 year old boy, injected cowpox into him Follwed by exposure to smallpox Vaccine was invented (latin vacca means ”cow”)
    3. 3. TYPES
    4. 4. 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
    5. 5.  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. Pathogens and disease Fungi Large parasites Protozoa Bacteria Viruses
    6. 6. 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.
    7. 7. 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.
    8. 8. T-Lymphocytes  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 δ chains.  The CD3 proteins and δ 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.
    9. 9. T cells express a number of other invariant functionassociated 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).
    10. 10. 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.
    11. 11. MHC Molecules  The 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.
    12. 12. 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.
    13. 13. 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.
    14. 14. 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).
    15. 15. 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.
    16. 16. 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.
    17. 17. Enzymatic Digestion Of Antibodies  Digestion With Papain Yields  3 Fragments  2 identical Fab and 1 Fc  Fab Because Fragment That is Antigen Binding  Fc Because Found To Crystallize In Cold Storage  Pepsin Digestion  F(ab`)2  No Fc Recovery, Digested Entirely  Mercaptoethanol Reduction (Eliminates Disulfide Bonds) And Alkylation Showed
    18. 18. There are five classes, or isotypes, of immunoglobulins
    19. 19. Antibody Classes And Biological Activities  IgG  Most abundant immunoglobin 80% of      serum Ig ~10mg/mL IgG1,2,3,4 (decreasing serum concentration) IgG1, IgG3 and IgG4 cross placenta IgG3 Most effective complement activator IgG1 and IgG3 High affinity for FcR on phagocytic cells, good for opsonization
    20. 20. Antibody Classes And Biological Activities  IgM  5-10% of serum immunoglobulin  1.5mg/mL  mIgM (also IgD) expressed on B-cells as     BCR Pentameric version is secreted First Ig of primary immune response High valence Ig (10 theoretical), 5 empirical More efficient than IgG in complement activation
    21. 21. Antibody Classes And Biological Activities  IgA  10-15% of serum IgG  Predominant Ig in secretions ○ Milk, saliva, tears, mucus  5-15 g of IgA released in secretions!!!!  Serum mainly monomeric, polymers possible not common though  Secretions, as dimer or tetramer+J-chain polyptetide+secretory component (Poly IgR)
    22. 22. IgA Antibody Transport Across Cell (Transcytosis)
    23. 23. Antibody Classes And Biological Activities  IgE  Very low serum concentration, 0.3g/mL  Participate in immediate hypersensitivities reations. Ex. Asthma, anaphylaxis, hives Binds Mast Cells and Blood Basophils thru FcR  Binding causes degranulation (Histamine Release) 
    24. 24. 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, ~30g/mL 
    25. 25. Cross-Linkage of Bound IgE Antibody With Allergen Causes
    26. 26. Mechanisms of Action of Antibodies Antibodies 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
    27. 27. Type Number of ag binding sites Site of action Functions IgG 2 •Blood •Tissue fluid •CAN CROSS PLACENTA IgM 10 •Blood •Tissue fluid Agglutination 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 IgA •Increase macrophage activity •Antitoxins •Agglutination
    28. 28. Cell-mediated immunity
    29. 29. Humoral immunity
    30. 30. 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.
    31. 31. Hypersensitivity reactions – originally divided into 2 categories: immediate and delayed I. Immidiate type  Reaction occurs immediately within sec/min after Ag exposer.  Mediated by humoral Ab.  Further divided 3 types  Type 1, 2 & 3. II. Delayed type Reaction slower in onset and develops within 24-48 hrs and effects are prolonged Mediated by cellular response.
    32. 32. Mechanisms of Immunologically Mediated Diseases Type Prototype Disorder Immediate (type Anaphylaxis, allergies, I) hypersensitivity bronchial asthma Immune Mechanisms Production of IgE antibody, immediate release of vasoactive amines and other mediators from mast cells; recruitment of inflammatory cells (late-phase reaction) Pathologic Lesions Vascular dilation, edema, smooth muscle contraction, mucus production, inflammation AntibodyAutoimmune hemolytic Production of IgG, IgM →binds to Phagocytosis and lysis of mediated (type II) anemia; Goodpasture antigen on target cell or tissue, cells; inflammation; in hypersensitivity syndrome phagocytosis or lysis of target cell some diseases, functional by activated complement or Fc derangements without receptors; recruitment of cell or tissue injury leukocytes Immune Systemic lupus complexerythematosus; some mediated (type III) forms of Deposition of antigen-antibody complexes →complement activation →recruitment of Inflammation, necrotizing vasculitis (fibrinoid necrosis)
    33. 33. 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).
    34. 34. Sequence of events in immediate (type 1) hypersensitivity
    35. 35. Action Mediator Vasodilation, increased vascular permeability Histamine PAF Leukotrienes C4, D4, E4 Neutral proteases that activate complement and kinins Prostaglandin D2 Smooth muscle spasm Leukotrienes C4, D4, E4 Histamine Prostaglandins PAF Cellular infiltration Cytokines (e.g., chemokines, TNF) Leukotriene B4
    36. 36. 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.
    37. 37. Mechanisms of Antibody-Mediated Diseases
    38. 38. 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 C leukocytes and by complement breakdown products. , 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
    39. 39. Examples of Antibody-Mediated Diseases (Type II Hypersensitivity) Mechanisms of Disease Disease Target Antigen Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Erythrocyte membrane Opsonization and proteins (Rh blood group phagocytosis of antigens, I antigen) erythrocytes Platelet membrane Opsonization and proteins (gpllb:Illa integrin) phagocytosis of platelets Pemphigus vulgaris Proteins in intercellular Antibody-mediated Skin vesicles junctions of epidermal activation of (bullae) cells (epidermal cadherin) proteases, disruption of intercellular adhesions Manifestations Hemolysis, anemia Bleeding
    40. 40. Acute Streptococcal cell wall Inflammation, macrophage rheumatic fever antigen; antibody activation cross-reacts with myocardial antigen Myasthenia gravis Myocarditis, arthritis Acetylcholine receptor Antibody inhibits Muscle acetylcholine binding, down- weakness, modulates receptors paralysis Graves disease TSH receptor (hyperthyroidis m) Antibody-mediated Hyperthyroi stimulation of TSH receptors dism Insulinresistant diabetes Antibody inhibits binding of Hyperglyce insulin mia, ketoacidosis Insulin receptor
    41. 41. 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 antigensnucleoproteins. 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.
    42. 42. 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.
    43. 43. Systemic Immune Complex Disease The pathogenesis of systemic immune complex disease can be divided into three phases The sequential phases in the induction of systemic immune complex mediate- d diseases (type III hyper- sensitivity).
    44. 44. 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).
    45. 45. 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.
    46. 46. Examples of Immune Complex-Mediated Diseases Clinicopathologic Manifestations Disease Antigen Involved Systemic lupus erythematosus Nuclear antigens Poststreptococcal glomerulonephritis Streptococcal cell wall Nephritis antigen(s); may be "planted" in glomerular basement membrane Polyarteritis nodosa Hepatitis B virus antigen Nephritis, skin lesions, arthritis, others Systemic vasculitis
    47. 47. T-Cell-Mediated (Type IV) Hypersensitivity Cell 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.
    48. 48. 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.
    49. 49. 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.
    50. 50. 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).
    51. 51. 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
    52. 52. 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 selfreactive cells.
    53. 53.  Immature B cells that recognize, with high affinity, selfantigens 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 selfantigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals
    54. 54. o Peripheral 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
    55. 55. 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 selfantigen 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 selfreactive B cells by Fas ligand expressed on helper T cells.
    56. 56. 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 Autoimmunity  The 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
    57. 57. Genetic Factors in Autoimmunity There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases Expression of a particular MHC gene variable that can contribute to autoimmunity. Disease Ankylosing spondylitis Postgonococcal arthritis Acute anterior uveitis Rheumatoid arthritis Autoimmune hepatitis Primary Sjögren syndrome Type 1 diabetes mellitus Relative Risk HLA Allele (approximate %) B27 90-100 B27 14 B27 15 DR4 4 DR3 14 DR3 10 DR3 5
    58. 58. 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.
    59. 59. 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
    60. 60. 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 celland 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.
    61. 61. Mechanism Rejection 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
    62. 62. Direct 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.
    63. 63. 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.