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Ocular Immunology/ Uveitis Kyle C. McKenna, Ph. D. Associate Professor of Biology and Ophthalmology [email protected] Hypopyon Ocular infiltrate of white blood cells (leukocytes) which settle via gravity to the bottom of the anterior chamber “like sands through the hour glass” How did the leukocytes get there? Leukocytes (cells of the immune system travel Via blood and enter the eye via vessels in the iris, ciliary body, choroid, retina, and sclera 4 Basophil Band Cell Blood Smear 6 3 1 5 Eosinophil Neutrophil Lymphocyte Lymphocyte 5 Neutrophil 1 Monocyte 2 Innate Immunity Neutrophil Eosinophil Adaptive Immunity Basophil Granulocytes Monocytes Lymphocytes T Cells B Cells Mast Cells Macrophages ab T gd T Complement CD4+ Thelper CD8+ CTL Antibody Innate • Immediate • Includes anatomical and biochemical barriers • Recognition of conserved pathogen associated molecular patterns (PAMPs) • No memory generation Adaptive • Delayed • Specific recognition of pathogenic molecules • Memory Generation PAMP PRR Pathogen Recognition Receptor Lipopolysaccharide (LPS) TLR 4 Toll Like Receptor Double Stranded RNA TLR 3 DAMP DRR Damage associated molecular pattern Damage Recognition Receptor HMGB1 RAGE, TLR 2, 4 and 9 (High Mobility Group box 1) Receptor of advanced glycation endproduct Nonoxidized (reduced) HMGB1 is released by normal cells upon necrotic but Not apoptotic cell death PAMPs and DAMPs promote inflammation Redness SWELLING IL-1 IL-6 TNFa Nitric oxide IL-8 PAIN Activated Antigen Presenting Cells Leave via afferent lymphatics Macs DC Increased Cell Surface molecules MHC Class I & II CD40, CD80, CD86 Produce inflammatory cytokines IL-12 TNFa Secondary Lymphoid Organs Spleen Innate immunity is immediate but alone insufficient for pathogen control Adaptive Immunity B-Cells Immunoglobulin Antigen Receptor: Proteins, Carbohydrates Recognition: Lipids, most any molecule T-Cells TCR Processed Proteins Presented as Peptides via MHC molecules by APC Exogenous Proteins via MHC Class II Endogenous Proteins via MHC Class I Professional APC All Cells in Body From Eye APC Free Antigen T T T T B T B T B T B T FDC B B T B B B T T T T T More Proliferation Here Clonal Expansion APC Differentiation Antibody Secreting Plasma Cells T helper Subsets Diverse Repertoire Of B cells and T cell Increase Numbers Of Antigen Specific Clones CTL Memory Cells Process of Expansion and Differentiation takes time which is why AdaptiveImmunity is Delayed Lytic granules Containing Granzyme B CD8+ CTL Lysis of infected Cells What determines unique Thelper differentiation? IL-2 IFNg PAMPS / APC APC LPS/TLR4 IL-4 IL-12 CD4+ T helper IFNg ? Filaria IL-4, 5, 6, 10 IL-2 TH1 APC TH2 B cells B cells IgG2a Viral and Bacterial infections IgG, IgE Extracellular Helminthic Infections Infections Activate Innate Immunity via PAMPS Activated APC Leave eye Carrying Pathogenic Molecules Blood Stream Afferent Lymphatics Efferent Lymphatics T and B cell expansion And differentiation occur Lymph Node What is Type I Hypersensitivity? Immediate Hypersensitivity Antibody Mediated (IgE) IgE molecules are bound by FcEpsilon receptors on Mast Cells Mast Cells release histamines which promote inflammation Allergic Conjunctivitis What is Type II Hypersensitivity? Antibody Mediated Cell lysis via Antibody Dependent Cellular Cytotoxicity Comp MAC Rh Hemolytic anemia in newborns Sympathetic ophthalmia, Uveitis Phagocytosis What is Type III Hypersensitivity? Antibody Complex Mediated Antibody Complexes Fix Complement Leading to production Of anaphylotoxins which promote inflammation Comp MAC Comp MAC Comp MAC C3a, C5a Anaphlotoxins Promote vasodilation And leukocyte infiltration What is Type IV Hypersensitivity? Delayed Type Hypersensitivity T cell mediated (CD4 TH1 cells) CD4+ T cells activate macrophages to release inflammatory mediators (TNFa, Nitric Oxide) which causes nonspecific damage of innocent bystander Tissues Promote infiltration of neutrophils which further enhance inflammation IFNg CD4+ T helper MAC Nitric Oxide TNFa What is Type V Hypersensitivity? Antibodies are generated which are stimulatory Graves Disease Anti-thyroid stimulating hormone receptor antibodies stimulate the effects of Thyroid Stimulating Hormone TSH TSHR Antibody TCR and Immunoglobulin molecules are generated by Random Somatic Rearrangement of gene segments What is the potential complication of this process? Generation of TCR and Immunoglobulin molecules that recognize self tissues T cells expressing TCR with strong reactivity to self antigens are deleted In the Thymus during T cell development What is the consequence of overly stringent negative selection? Decreased Repertoire of the T cell pool Fact: T cells and B cells are generated with receptors that demonstrate some affinity for self antigens. Why are we not in a constant state of autoimmunity? Peripheral tolerance mechanisms Three Signals are Required for Full T cell activation 3 1. TCR : MHC/peptide 2. Costimulatory Molecules 3. Cytokine Production In the absence of three signals T cell anergy or tolerance is generated Cytokines How do PAMPS break tolerance to Self antigens? PAMPS increase costimulatory molecules And cytokine expression Uveitis Classic T cell dependent Type IV hypersensitivity response Infectious (syphilis, tuberculosis, toxoplasma gondii) Noninfectious (self antigens) [mouse models via immunization with IRBP, Retinal S-ag] Disease Associations made with particular MHC molecules HLA-B27 : Reiter’s syndrome HLA-B5: Behcet’s Disease HLA-29: Birdshot Choroidopathy How could an immune response to an ocular antigen develop to Cause autoimmune uveitis? Retention of T cells with specificity to ocular antigens due to Weak negative selection in individuals with particular HLA types Previous infection or trauma primed for ocular antigens in an Inflammatory context Molecular Mimicry (Klebsiella, Chlymidia, Yersinia?) Ocular Immune Privilege Characterized by prolonged acceptance of foreign immunogenic grafts In comparison to conventional sites Corneal Allografts most successful (no matching, minimal immunosuppression required) Experimentally immunogenic tumors grow progressively in the anterior Chamber but are eliminated by CD8+ T cells when transplanted in the skin Anatomical Barriers to Host Immune Response Cornea is avascular Interior of Eye lacks demonstrable lymphatic drainage Blood Aqueous Barrier Blood Retinal Barrier Biochemical Barriers to Host Immune Response Aqueous Humor contains Immunosuppressive soluble factors (TGF-b, a-MSH, IL-10, MIF, CGRP, VIP, somatostatin) Interior Cell Surface expresses Death inducing Molecules (FasL, Trail, PD-1 and PD-2L) T cell anergy, T cell death, T regulatory generation Tolerance Induction to Ocular Antigens Introduction of foreign antigens into the anterior chamber, subretinal space And vitreous cavity induces systemic tolerance to these antigens Mediated by the generation of Tregulatory cells CD4, CD8+