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

1. IMMUNOLOGY OF THE EYE Dr. MrinmayeeGhatak P.G., Dept of Ophthalmology, K.I.M.S. Hospital, Bangalore Email: dr.mrin@gmail.com

3. IMMUNE SYSTEM: the collection of cells, tissues and molecules that mediate resistance to diseases

4. IMMUNE RESPONSE: the coordinated reaction of these cells and molecules for producing resistance to diseases

7. Natural or native immunity

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. Adaptive :

10. Specific or acquired immunity

18. Cells of the Immune System

20. Found in :

21. lymph node, spleen, thymus, gut-associated lymphoid tissue, mammary-associated lymphoid tissue, and conjunctiva-associated lymphoid tissue

22. And blood

23. 30% of the total peripheral white blood cell count

24. premier character in the immune drama

26. LYMPHOCYTES Types of lymphocytes: T-lymphocytes : Helper (CD4) T cells Cytotoxic (CD8) T cells B-lymphocytes : (IgG, IgA, IgM, IgD, IgE) Null Cells Natural Killer Cells

29. High density of class II MHC glycoproteins

30. Receptors for :

31. Complement components, Fc portion of Ig molecules

32. Fibronectin, Interferons, TNF, M-CSF

33. Synthesize and secrete:

34. Proteases, collagenase, lysosyme

35. INF-alpha, INF-beta, IL-6, YNF-alpha, fibronectic

36. IGF-beta, PDGF, M-CSF, G-CSF, GM-CSF, PAF,

38. LANGERHANS’ CELLS Premier APC for external eye rich in class II MHC molecules Abundant in corneo-scleral limbus, less in peripheral cornea, absent from central 1/3rd of cornea

40. POLYMORPHENUCLEAR LEUKOCYTES (PMNs) Central to host defences through phagosytosis Categorized as: Neutrophils Basophils Eosinophils

41. NUEUTROPHILS Account for 90% granulocytes Stimulated by chemotactic agents: Complement components Fibrinolytic & kinin system components Products from other leucocytes, platelets

42. NUEUTROPHILS Release their contents & result in : Phagocytosis of micro-organisms Type II antibody-dependent cell-mediated cytotoxicity Type III hypersensitivity reactions (immune-complex-mediated diseases)

43. EOSINOPHILS 3-5% of circulating PMNs Special role in : Type 1 hypersensitivity - Allergic conditions & parasitoses Type III hypersensitivity reactions

44. BASOPHILS < 0.2% of circulating PMNs As tissue mast cells

45. MAST CELLS Indistinguishable from basophils Predominant cells in type 1 hysersensitivity - allergic responses Also participate in Type II, III, IV hypersensitivity reactions (role not clear) 2 types: Mucosal Mast Cells Connective Tissue Mast Cells

46. PLATELETS Cells for blood clotting Involved in immune response to injury: Adhere to & aggregate at the endothelial surface Release prermeability-increasing molecules Cause type III hypersensitivity reaction: Antigen-antibody immune complex > Activation of mast cells > release of Platelet-activating factor > activation of platelets

48. If T cells are present > entire array of immune responses & tolerance possible

49. If T cells are absent > only primitive antibody response is possible, no Cell-mediated response

50. Differentiate mostly in thymus gland with specific goals:

51. Acquire unique surface receptor for antigen

52. Cells that recognize foreign antigen > positively selected

53. Cells that recognize self-antigen > negatively selected

55. Functions of TH1 and TH2 cells in the immune response via the release of cytokines

56. Generation of cytokines by endothelial cells,fibroblasts, T-helper lymphocytes, and monocytemacrophages

57. T-LYMPHOCYTE RESPONSES

58. B-LYMPHOCYTE RESPONSE

59. B-LYMPHOCYTE RESPONSE

60. Non-specific Humoraldefence mechanisms

61. Hazards of Immunity Inadvertent injury to normal host tissues Development of Autoimmunity

62. Special Case of the Eye :Immune Privilege Dilemma of the eye: Needs to be protected Prevent injury to normal tissues Certain forms of immunity are permitted and others are suppressed

63. Immune Privileged Sites 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: Cornea Anterior chamber Lens Vitreous cavity Subretinal space

65. Blood-tissue barriers

66. Deficient efferent lymphatics

67. Reduced expression of major histocompatibility complex class I and II molecules

68. Active

69. Expression of inhibitory cell surface molecules: Fasligand, DAF, CD59, CD46

71. Establishment of Ocular Immune Privilege Three different strategies : Immunologic Ignorance Peripheral tolerance to ocular-derived antigens Development of an intraocular immunosuppressive microenvironment.

74. Central & Peripheral Tolerance to Self-Antigens 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)

75. Intraocular immunosuppressive microenvironment There are also local factors within the eye that inhibit the components of the immune response to reinforce the protection provided by immune privilege.

76. Immunosuppressive and anti-inflammatory factors in AH

77. CORNEAL TRANSPLANTATION : ACCEPTED OR REJECTED Immune privilege plays an important role Factors that help in prevailing immune privilege : Reduced & impaired expression of MHC class I and II molecules in corneal cells. Thus the net antigenic load is reduced. Cornea lacks both blood & lymph vessels. Prevents antigenic information escaping from tissues and migration of APC.

78. Cornea is deficient in Bone-marrow derived cells (Langerhans Cells). Absence of APC lengthens the time for graft recognisation. Secretion of molecules with immunosuppressive properties to inhibit macrophages, NK cells, APC, T cells, B cells. Expression of surface molecules that inhibit immune effectors. ACAID in recepients

80. Immune-privilege & angiogenic-privilege both are present

81. No lymphoid cells under physiological conditions

82. MHC class II presenting Langerhans’ cells only in peripheral cornea

83. Few bone-marrow derived macrophage-like cells in anterior and posterior stroma

84. CONJUNCTIVA:

85. Lamina-propria rich in CALT

86. Presence of specialized endothelial venules for regulated migration of lymphoid cells

87. Diffuse lymphoid populations in all conjunctival zones (lymphocytes (CD4, CD8 cells) & plasma cells (IgA secretion)

88. Macrophages, dendriticLangerhans’ cells, mast cells frequent in lamina propria

90. ANATOMY OF THE IMMUNE SYSTEM AT THE OCULAR SURFACE TEAR FILM & INTEGRATED PROTEINS: Specific IgA antibodies Lysozymes : destroy bacterial cell wall Lactoferrin : binds iron Tear-specific prealbumin : scavenger of bacterial products Angiogenin : antimicrobial effect within tear film Others antimicrobial molecules to recruit leucocytes: Specific leucocyte-protease inhibitor, Interleukin-8 IF-gamma-inducible protein, Macrophage inhibitory protein IL-6, macrophage-CSF

91. MUCOSAL IMMUNE DEFENSE MECHANISMS AT THE OCULAR SURFACE 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.

92. Mucosal, like systemic, immunity uses two approaches for defense, the innate and the adaptive immune system.

93. Innate immunity at ocular surface Evolutionary Old system : detection and destruction of microbial pathogens Phagocytes, macrophages, Langerhans’ cells, neutrophils, mast cells Chemokines and specific antimicrobial peptides like Beta-Defensin, Collectins, bactericidal permeability-increasing protein, etc

94. Specific adaptive immunity at the ocular surface Lymphoid cells with high degree of specificity, variability, and immune regulation Afferent antigen uptake & processing Recognition of antigens Differentiation & proliferation of lymphocytes Action of effector lymphocytes

96. DEFENCE STRATEGIES AT OCULAR SURFACE The Immune Privilege Approach : Predominant at day time The Proinflammatory Approach : Predominant at night time

100. Gell-Cooms-LackmannHypersensitivity Reactions

103. Inappropriate inflammatory responses to ubiquitous environmental agents

104. Antigens responsible :

105. dust, pollens, danders, microbes, and drugs

106. Antibodies involved :

107. antibodies, principally IgE

108. Mediators of the clinical manifestations :

109. Histamine

110. Serotonin

111. Leukotrienes

112. Kinins

115. Biochemical events in Mast Cell Activation

116. Three genetically linked mechanisms: General hyper-responsiveness : positive skin reactions to a broad range of environmental allergens Regulation of serum IgE levels Sensitivity to specific antigens

117. THERAPY OF TYPE I REACTIONS Environmental control Mast cell stabilizers Systemic antihistamines Topical steroids (for acute intervention only) Desensitization immunotherapy Plasmapheresis Intravenous gamma globulin Cyclosporine (systemic and topical) Psychiatric intervention for the patient and family

119. Type II Hypersensitivity Reaction 3 types: Antibody- and complement-mediated lysis Antibody dependent cell-mediated cytotoxicity inhibition of transmission of the nerve impulse by antibodies

120. Antibody- and complement-mediatedlysis of a nucleated cell as a consequence of formation of the membrane attack complex Antibody dependent cell-mediated cytotoxicity through the action of either an NK or a K cell with surface antibody specific for a target cell Inhibition of transmission of the nerve impulse by antibodies against acetycholine receptors as occurs in myasthenia gravis

122. THERAPY FOR TYPE II REACTIONS immunosuppressive chemotherapy has been the mainstay of treatment

123. Type III Hypersensitivity Reaction Schematic representation of the formation and deposition of immune complexes in vessel walls in type III hypersensitivity

124. THERAPY FOR TYPE III REACTIONS large doses of corticosteroids, of immunosuppressive chemotherapeutic agents, or both

126. Two types of reactions :

127. Delayed-type hypersensitivity (DTH) is mediated by CD4+ T cells

129. effect on the specific target cell through one ofthree routes

132. THERAPY FOR TYPE IV REACTIONS

134. Autoantigensare normal body constituents recognized by autoantibodies specific for them.

135. An autoantibody recognizes and interacts with an antigen present as a natural component of the individual synthesizing the autoantibody

138. Postulated mechanism for Autoimmunity Various genetic loci may confer susseptibility to autoimmunity, probably by influencing the maintainance of self-tolerance. 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

139. Sequestered Antigen Anatomically isolated Not in contact with the T and B lymphoid cells Examples : myelin basic protein sperm antigens Crystalline lens protein antigens. When released, it can activate both T and B cells.

140. Organ specific Autoimmune Diseases Autoimmune thyroiditis Drug-induced immune hemolytic anemia Autoimmune lymphoproliferative syndrome Autoimmune thrombocytopenic purpura Pernicious Anemia Idiopathic thrombocytopenic purpura Autoimmune gastritis, Chronic active autoimmune hepatitis Primary sclerosing cholangitis Goodpasture syndrome IDDM Pemphigus vulgaris, phemphigoid Systemic lupus erythematosus (SLE), RA, JRA Sjögren’s syndrome, Scleroderma, Polymyositis HLA-B27-related arthropathies

141. Ocular Autoimmune Diseases Autoimmune Uveoretinitis Dalen-Fuchs nodule Endophthalmitis phacoanaphylactica Keratoconjunctivitis sicca Lens-induced uveitis Postinfectious iridocyclitis Retina autoantibodies Sympathetic ophthalmia

142. Ocular Diseases in which a Defect in Immunoregulation Plays a Role

143. Thank You