Immunology Of The Eye

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This presentation gives detailed view of immunological aspects of the eye. This will be very helpful for all graduates and ophthalmologists.

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Immunology Of The Eye

  1. 1. IMMUNOLOGY OF THE EYE<br />Dr. MrinmayeeGhatak<br />P.G., Dept of Ophthalmology,<br />K.I.M.S. Hospital,<br />Bangalore<br />Email: dr.mrin@gmail.com<br />
  2. 2. IMMUNITY<br /><ul><li>IMMUNITY :Resistance to diseases specially infectious
  3. 3. IMMUNE SYSTEM: the collection of cells, tissues and molecules that mediate resistance to diseases
  4. 4. IMMUNE RESPONSE: the coordinated reaction of these cells and molecules for producing resistance to diseases
  5. 5. IMMUNOLOGY: study of the immune system and its response to the invading pathogens</li></li></ul><li>Importance of Immune System<br />
  6. 6. Types of Immunity<br /><ul><li>Innate:
  7. 7. Natural or native immunity
  8. 8. This type of host defense is always present in healthy individuals, prepared to block the entry of microbes and to rapidly eliminate microbes that do succeed in entering the host tissues
  9. 9. Adaptive :
  10. 10. Specific or acquired immunity
  11. 11. Type of host defense that is stimulated by microbes that invade tissues, that is, it adapts to the presence of microbial invaders</li></li></ul><li>Cardinal features of Adaptive Immunity<br />Acquired<br />Absolutely specific<br />Learned (anamnestic response)<br />Transferable<br />Tolerant<br />
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. 16.
  17. 17.
  18. 18. Cells of the Immune System<br />
  19. 19. LYMPHOCYTES<br /><ul><li>Mononuclear cells
  20. 20. Found in :
  21. 21. lymph node, spleen, thymus, gut-associated lymphoid tissue, mammary-associated lymphoid tissue, and conjunctiva-associated lymphoid tissue
  22. 22. And blood
  23. 23. 30% of the total peripheral white blood cell count
  24. 24. premier character in the immune drama
  25. 25. cell exclusively responsible for immune memory</li></li></ul><li>
  26. 26. LYMPHOCYTES<br />Types of lymphocytes:<br />T-lymphocytes :<br />Helper (CD4) T cells<br />Cytotoxic (CD8) T cells<br />B-lymphocytes : (IgG, IgA, IgM, IgD, IgE)<br />Null Cells<br />Natural Killer Cells<br />
  27. 27.
  28. 28. MACROPHAGES<br /><ul><li>“Large eater” – preeminent professional APC
  29. 29. High density of class II MHC glycoproteins
  30. 30. Receptors for :
  31. 31. Complement components, Fc portion of Ig molecules
  32. 32. Fibronectin, Interferons, TNF, M-CSF
  33. 33. Synthesize and secrete:
  34. 34. Proteases, collagenase, lysosyme
  35. 35. INF-alpha, INF-beta, IL-6, YNF-alpha, fibronectic
  36. 36. IGF-beta, PDGF, M-CSF, G-CSF, GM-CSF, PAF,
  37. 37. Prostaglandins, LK, oxygen metabolites</li></li></ul><li>MACROPHAGES<br />Specialized macrophages:<br />Histiocytes<br />Kupffer cell of liver<br />Dendritic histiocytes and Interdigitating reticulum cells in lymphoid organs<br />Langerhans’ cells in skin and lymph nodes<br />Langerhans’ cells in conjunctiva & cornea<br />
  38. 38. LANGERHANS’ CELLS<br />Premier APC for external eye<br />rich in class II MHC molecules<br />Abundant in corneo-scleral limbus, less in peripheral cornea, absent from central 1/3rd of cornea<br />
  39. 39.
  40. 40. POLYMORPHENUCLEAR LEUKOCYTES (PMNs)<br />Central to host defences through phagosytosis<br />Categorized as:<br />Neutrophils<br />Basophils<br />Eosinophils<br />
  41. 41. NUEUTROPHILS<br />Account for 90% granulocytes<br />Stimulated by chemotactic agents:<br />Complement components<br />Fibrinolytic & kinin system components<br />Products from other leucocytes, platelets<br />
  42. 42. NUEUTROPHILS<br />Release their contents & result in :<br />Phagocytosis of micro-organisms<br />Type II antibody-dependent cell-mediated cytotoxicity<br />Type III hypersensitivity reactions (immune-complex-mediated diseases)<br />
  43. 43. EOSINOPHILS<br />3-5% of circulating PMNs<br />Special role in :<br />Type 1 hypersensitivity - Allergic conditions & parasitoses<br />Type III hypersensitivity reactions<br />
  44. 44. BASOPHILS<br />&lt; 0.2% of circulating PMNs<br />As tissue mast cells<br />
  45. 45. MAST CELLS<br />Indistinguishable from basophils<br />Predominant cells in type 1 hysersensitivity - allergic responses<br />Also participate in Type II, III, IV hypersensitivity reactions (role not clear)<br />2 types:<br />Mucosal Mast Cells<br />Connective Tissue Mast Cells<br />
  46. 46. PLATELETS<br />Cells for blood clotting<br />Involved in immune response to injury:<br />Adhere to & aggregate at the endothelial surface<br />Release prermeability-increasing molecules<br />Cause type III hypersensitivity reaction:<br />Antigen-antibody immune complex &gt; Activation of mast cells &gt; release of Platelet-activating factor &gt; activation of platelets <br />
  47. 47. T-LYMPHOCYTE RESPONSES<br /><ul><li>Most important cells of adaptive immune response
  48. 48. If T cells are present > entire array of immune responses & tolerance possible
  49. 49. If T cells are absent > only primitive antibody response is possible, no Cell-mediated response
  50. 50. Differentiate mostly in thymus gland with specific goals:
  51. 51. Acquire unique surface receptor for antigen
  52. 52. Cells that recognize foreign antigen > positively selected
  53. 53. Cells that recognize self-antigen > negatively selected
  54. 54. Each mature cell acquires unique effector functions</li></li></ul><li>
  55. 55. Functions of<br />TH1 and TH2 cells<br />in the<br />immune response<br />via the<br />release of cytokines<br />
  56. 56. Generation of cytokines by endothelial cells,fibroblasts, T-helper lymphocytes, and monocytemacrophages<br />
  57. 57. T-LYMPHOCYTE RESPONSES<br />
  58. 58. B-LYMPHOCYTE RESPONSE<br />
  59. 59. B-LYMPHOCYTE RESPONSE<br />
  60. 60. Non-specific Humoraldefence mechanisms<br />
  61. 61. Hazards of Immunity<br />Inadvertent injury to normal host tissues<br />Development of Autoimmunity<br />
  62. 62. Special Case of the Eye :Immune Privilege<br />Dilemma of the eye:<br />Needs to be protected<br />Prevent injury to normal tissues<br />Certain forms of immunity are permitted and others are suppressed<br />
  63. 63. Immune Privileged Sites<br />Sites in the body where foreign tissue grafts can survive for extended periods of time whereas similar grafts placed in conventional sites are acutely rejected by the host:<br />Cornea<br />Anterior chamber<br />Lens<br />Vitreous cavity<br />Subretinal space<br />
  64. 64. Features of Immune Privileged Sites<br /><ul><li>Passive
  65. 65. Blood-tissue barriers
  66. 66. Deficient efferent lymphatics
  67. 67. Reduced expression of major histocompatibility complex class I and II molecules
  68. 68. Active
  69. 69. Expression of inhibitory cell surface molecules: Fasligand, DAF, CD59, CD46
  70. 70. Immunosuppressive microenvironment: TGFb, a-MSH, VIP, CGRP, MIF, free cortisol</li></li></ul><li>Anterior Chamber Associated Immune Deviation<br />Actively acquired and maintained state in which ocular factors, acting on cells of the immune system, suppress the expression of immunity within the eye and alter the induction of systemic immunity to ocular antigens, leading to a stereotypic systemic immune response called anterior chamber associated immune deviation (ACAID)<br />
  71. 71. Establishment of Ocular Immune Privilege<br />Three different strategies :<br />Immunologic Ignorance<br />Peripheral tolerance to ocular-derived antigens<br />Development of an intraocular immunosuppressive microenvironment.<br />
  72. 72. Immunologic Ignorance<br /><ul><li>Corneal cells has reduced expression of MHC class 1 molecules and do not express MHC class II molecules
  73. 73. the normal cornea lacks blood & lymphatic vessels </li></li></ul><li>Peripheral tolerance to ocular-derived antigens<br />The immunologic hallmarks of ACAID include the generation of primed cytotoxic (CD8) T and B cells that produce non-complement-fixing antibodies, as well as the inhibition of delayed-type hypersensitivity (CD4 Th1) and B cells that secrete complement-fixing antibodies.<br />
  74. 74. Central & Peripheral Tolerance to Self-Antigens<br />Immature lymphocytes specific for self-antigens may encounter these antigens in the generative lymphoid organs and are deleted (central tolerance). Mature self-reactive lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral tissues (peripheral tolerance)<br />
  75. 75. Intraocular immunosuppressive microenvironment<br />There are also local factors within the eye that inhibit the components of the immune response to reinforce the protection provided by immune privilege.<br />
  76. 76. Immunosuppressive and anti-inflammatory factors in AH<br />
  77. 77. CORNEAL TRANSPLANTATION : ACCEPTED OR REJECTED<br />Immune privilege plays an important role<br />Factors that help in prevailing immune privilege :<br />Reduced & impaired expression of MHC class I and II molecules in corneal cells. Thus the net antigenic load is reduced.<br />Cornea lacks both blood & lymph vessels. Prevents antigenic information escaping from tissues and migration of APC.<br />
  78. 78. Cornea is deficient in Bone-marrow derived cells (Langerhans Cells). Absence of APC lengthens the time for graft recognisation.<br />Secretion of molecules with immunosuppressive properties to inhibit macrophages, NK cells, APC, T cells, B cells.<br />Expression of surface molecules that inhibit immune effectors.<br />ACAID in recepients<br />
  79. 79. ANATOMY OF THE IMMUNE SYSTEM AT THE OCULAR SURFACE<br /><ul><li>CORNEA
  80. 80. Immune-privilege & angiogenic-privilege both are present
  81. 81. No lymphoid cells under physiological conditions
  82. 82. MHC class II presenting Langerhans’ cells only in peripheral cornea
  83. 83. Few bone-marrow derived macrophage-like cells in anterior and posterior stroma
  84. 84. CONJUNCTIVA:
  85. 85. Lamina-propria rich in CALT
  86. 86. Presence of specialized endothelial venules for regulated migration of lymphoid cells
  87. 87. Diffuse lymphoid populations in all conjunctival zones (lymphocytes (CD4, CD8 cells) & plasma cells (IgA secretion)
  88. 88. Macrophages, dendriticLangerhans’ cells, mast cells frequent in lamina propria
  89. 89. Granulocytes emigrate only if recruited during immune response</li></li></ul><li>ANATOMY OF THE IMMUNE SYSTEM AT THE OCULAR SURFACE<br />CONJUNCTIVA:<br />Lymphoid follicles with B cells & parafollicular T cells normally present<br />LACRIMAL GLAND:<br />More plasma cells (IgA) & CD8 cells compared to conjunctiva<br />T cells in small groups around intralobular ducts<br />Rest lymphoid cells very rarely observed<br />LACRIMAL DRAINAGE SYSTEM :<br />Diffue lymphoid tissue and follicles (40-50%) in mucosa<br />
  90. 90. ANATOMY OF THE IMMUNE SYSTEM AT THE OCULAR SURFACE<br />TEAR FILM & INTEGRATED PROTEINS:<br />Specific IgA antibodies<br />Lysozymes : destroy bacterial cell wall<br />Lactoferrin : binds iron<br />Tear-specific prealbumin : scavenger of bacterial products<br />Angiogenin : antimicrobial effect within tear film<br />Others antimicrobial molecules to recruit leucocytes:<br />Specific leucocyte-protease inhibitor, Interleukin-8<br />IF-gamma-inducible protein, Macrophage inhibitory protein<br />IL-6, macrophage-CSF<br />
  91. 91. MUCOSAL IMMUNE DEFENSE MECHANISMS AT THE OCULAR SURFACE<br />The eye-associated lymphoid tissue (EALT) is the mucosa-associated lymphoid tissue for immune protection of the ocular surface and its mucosal adnexa. It is anatomically continuous from the lacrimal gland throughout the conjunctiva- and lacrimal drainage-associated lymphoid tissue (i.e. CALT and LDALT, respectively). It consists of a diffuse lymphoid tissue of T lymphocytes and IgA-secreting plasma cells, including accessory leukocyte populations in all organs and of lymphoid follicles in conjunctiva- and lacrimal drainage-associated lymphoid tissue (in the drawing, large blue cells represent plasma cells, small blue cells represent B cells and small black cells represent T cells). Protective as well as aggressive factors inside the tear film, which connects the different parts of the ocular surface and protects it from the external environment, are a major component of ocular surface immunity. The organs are also connected by lymphocyte recirculation via specialized vessels with each other and with the rest of the immune system.<br />
  92. 92. Mucosal, like systemic, immunity uses two approaches for defense, the innate and the adaptive immune system.<br />
  93. 93. Innate immunity at ocular surface<br />Evolutionary Old system : detection and destruction of microbial pathogens<br />Phagocytes, macrophages, Langerhans’ cells, neutrophils, mast cells<br />Chemokines and specific antimicrobial peptides like Beta-Defensin, Collectins, bactericidal permeability-increasing protein, etc <br />
  94. 94. Specific adaptive immunity at the ocular surface<br />Lymphoid cells with high degree of specificity, variability, and immune regulation<br />Afferent antigen uptake & processing<br />Recognition of antigens<br />Differentiation & proliferation of lymphocytes<br />Action of effector lymphocytes<br />
  95. 95.
  96. 96. DEFENCE STRATEGIES AT OCULAR SURFACE<br />The Immune Privilege Approach :<br />Predominant at day time<br />The Proinflammatory Approach :<br />Predominant at night time<br />
  97. 97. Gell-Cooms-LackmannHypersensitivity Reactions<br /><ul><li>4 types are recognized based on mechanism of reaction
  98. 98. In real life the four types of hypersensitivity reactions rarely are observed in pure form, in isolation from each other</li></li></ul><li>
  99. 99.
  100. 100. Gell-Cooms-LackmannHypersensitivity Reactions<br />
  101. 101.
  102. 102. Type I Hypersensitivity Reaction<br /><ul><li>Cocoa and Cooke : ATOPY in 1923
  103. 103. Inappropriate inflammatory responses to ubiquitous environmental agents
  104. 104. Antigens responsible :
  105. 105. dust, pollens, danders, microbes, and drugs
  106. 106. Antibodies involved :
  107. 107. antibodies, principally IgE
  108. 108. Mediators of the clinical manifestations :
  109. 109. Histamine
  110. 110. Serotonin
  111. 111. Leukotrienes
  112. 112. Kinins
  113. 113. Other vasoactive amines</li></li></ul><li>A type I hypersensitivity reaction in which antigen molecules cross-link IgE molecules on the surface of mast cells, resulting in their degranulation with the relase of both primary and secondary mediators of anaphylaxis<br />
  114. 114. <ul><li>Mast Cell Mediators:</li></ul>Preformed in GranulesNewly Synthesized<br /> Histamine LTB4<br /> Heparin LTC4<br />Tryptase LTD4<br />Chymase Prostaglandins<br />KininsThromboxanes<br />Eosinophilchemotactic factor PAF<br />Neutrophilchemotactic factor<br /> Serotonin<br />Chondroitin sulfate<br />Arylsulfatase<br />
  115. 115. Biochemical events<br />in<br />Mast Cell Activation<br />
  116. 116. Three genetically linked mechanisms:<br />General hyper-responsiveness : positive skin reactions to a broad range of environmental allergens<br />Regulation of serum IgE levels<br />Sensitivity to specific antigens<br />
  117. 117. THERAPY OF TYPE I REACTIONS<br /> Environmental control<br /> Mast cell stabilizers<br /> Systemic antihistamines<br /> Topical steroids (for acute intervention only)<br /> Desensitization immunotherapy<br /> Plasmapheresis<br /> Intravenous gamma globulin<br /> Cyclosporine (systemic and topical)<br /> Psychiatric intervention for the patient and family<br />
  118. 118.
  119. 119. Type II Hypersensitivity Reaction<br />3 types:<br />Antibody- and complement-mediated lysis<br />Antibody dependent cell-mediated cytotoxicity<br />inhibition of transmission of the nerve impulse by antibodies<br />
  120. 120. Antibody- and complement-mediatedlysis of a nucleated cell as a consequence of formation of the membrane attack complex<br />Antibody dependent cell-mediated cytotoxicity through the action of either an NK or a K cell with surface antibody specific for a target cell<br />Inhibition of transmission of the nerve impulse by antibodies against acetycholine receptors as occurs in myasthenia gravis<br />
  121. 121.
  122. 122. THERAPY FOR TYPE II REACTIONS<br />immunosuppressive chemotherapy has been the mainstay of treatment<br />
  123. 123. Type III Hypersensitivity Reaction<br />Schematic representation of the formation and deposition of immune complexes in vessel walls in type III hypersensitivity<br />
  124. 124. THERAPY FOR TYPE III REACTIONS<br />large doses of corticosteroids, of immunosuppressive chemotherapeutic agents, or both<br />
  125. 125. Type IV Hypersensitivity Reaction<br /><ul><li>Whereas antibodies participate in type I, II, and III reactions, T lymphocytes mediate type IV hypersensitivity
  126. 126. Two types of reactions :
  127. 127. Delayed-type hypersensitivity (DTH) is mediated by CD4+ T cells
  128. 128. Cellular cytotoxicity is mediated principally by CD8+ T cells</li></li></ul><li>
  129. 129. effect on the specific target cell through one ofthree routes<br />
  130. 130.
  131. 131.
  132. 132. THERAPY FOR TYPE IV REACTIONS<br />
  133. 133. AUTOIMMUNITY<br /><ul><li>Autoimmunity is an immune reactivity involving either antibody-mediated (humoral) or cell-mediated limbs of the immune response against the body’s own (self) constituents
  134. 134. Autoantigensare normal body constituents recognized by autoantibodies specific for them.
  135. 135. An autoantibody recognizes and interacts with an antigen present as a natural component of the individual synthesizing the autoantibody
  136. 136. Autoallergyis a tissue injury or disease induced by immune reactivity against self antigens</li></li></ul><li>May be a consequence<br />May be organ-specific<br />Type I – IV hypersensitivity reactions<br />Autoimmune response should be considered as the cause of human disease if :<br />Regularly associated with that disease<br />Immunization of an experimental animal causes it to form antibodies or develop allergy<br />Animal develops pathological changes similar to humans<br />The experimental disease can be transferred to a nonimmunized animal by serum or by lymphoid cells<br />
  137. 137.
  138. 138. Postulated mechanism for Autoimmunity<br />Various genetic loci may confer susseptibility to autoimmunity, probably by influencing the maintainance of self-tolerance.<br />Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissue and the activation of self-reactive T cells, resulting in tissue injury<br />
  139. 139. Sequestered Antigen<br />Anatomically isolated <br />Not in contact with the T and B lymphoid cells <br />Examples :<br />myelin basic protein<br />sperm antigens<br />Crystalline lens protein antigens.<br />When released, it can activate both T and B cells.<br />
  140. 140. Organ specific Autoimmune Diseases<br />Autoimmune thyroiditis<br />Drug-induced immune hemolytic anemia<br />Autoimmune lymphoproliferative syndrome<br />Autoimmune thrombocytopenic purpura<br />Pernicious Anemia<br />Idiopathic thrombocytopenic purpura<br />Autoimmune gastritis, Chronic active autoimmune hepatitis<br />Primary sclerosing cholangitis<br />Goodpasture syndrome<br />IDDM<br />Pemphigus vulgaris, phemphigoid<br />Systemic lupus erythematosus (SLE), RA, JRA<br />Sjögren’s syndrome, Scleroderma, Polymyositis<br />HLA-B27-related arthropathies<br />
  141. 141. Ocular Autoimmune Diseases<br />Autoimmune Uveoretinitis<br />Dalen-Fuchs nodule<br />Endophthalmitis phacoanaphylactica<br />Keratoconjunctivitis sicca<br />Lens-induced uveitis<br />Postinfectious iridocyclitis<br />Retina autoantibodies<br />Sympathetic ophthalmia<br />
  142. 142. Ocular Diseases in which a Defect in Immunoregulation Plays a Role<br />
  143. 143. Thank You<br />

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