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Ocular Immunology/ Uveitis

Ocular Immunology/ Uveitis. Kyle C. McKenna, Ph. D. Associate Professor of Biology and Ophthalmology mckennakc@upmc.edu. Ocular infiltrate of white blood cells (leukocytes) which settle via gravity to the bottom of the anterior chamber “like sands through the hour glass”. Hypopyon.

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Ocular Immunology/ Uveitis

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  1. Ocular Immunology/ Uveitis Kyle C. McKenna, Ph. D. Associate Professor of Biology and Ophthalmology mckennakc@upmc.edu

  2. Ocular infiltrate of white blood cells (leukocytes) which settle via gravity to the bottom of the anterior chamber “like sands through the hour glass” Hypopyon 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

  3. Lymphocyte Neutrophil Lymphocyte Neutrophil 4 3 5 1 Basophil Eosinophil Band Cell Monocyte 5 2 6 Blood Smear 1

  4. Innate Immunity Adaptive Immunity Eosinophil Basophil Neutrophil Granulocytes Monocytes Lymphocytes T Cells B Cells Mast Cells ab T gd T Macrophages Complement CD4+ Thelper CD8+ CTL Antibody

  5. Immediate Includes anatomical and biochemical barriers Recognition of conserved pathogen associated molecular patterns (PAMPs) No memory generation Delayed Specific recognition of pathogenic molecules Memory Generation Adaptive Innate

  6. PRR Pathogen Recognition Receptor PAMP Lipopolysaccharide (LPS) TLR 4 Toll Like Receptor TLR 3 Double Stranded RNA DRR Damage Recognition Receptor DAMP Damage associated molecular pattern HMGB1 (High Mobility Group box 1) RAGE, TLR 2, 4 and 9 Receptor of advanced glycation endproduct Nonoxidized (reduced) HMGB1 is released by normal cells upon necrotic but Not apoptotic cell death

  7. Activated Antigen Presenting Cells Leave via afferent lymphatics Macs DC PAMPs and DAMPs promote inflammation Redness SWELLING PAIN IL-1 IL-6 TNFa Nitric oxide IL-8 Increased Cell Surface molecules MHC Class I & II CD40, CD80, CD86 Produce inflammatory cytokines IL-12 TNFa

  8. Secondary Lymphoid Organs Spleen

  9. Innate immunity is immediate but alone insufficient for pathogen control

  10. Adaptive Immunity B-Cells T-Cells Immunoglobulin TCR Antigen Receptor: Proteins, Carbohydrates Lipids, most any molecule Processed Proteins Presented as Peptides via MHC molecules by APC Recognition: Exogenous Proteins via MHC Class II Endogenous Proteins via MHC Class I Professional APC All Cells in Body

  11. From Eye APC Free Antigen

  12. T T T T B T B T B T B T B FDC B T B B B T T T T T More Proliferation Here

  13. Clonal Expansion APC Differentiation Antibody Secreting Plasma Cells Effectors T helper Subsets Increase Numbers Of Antigen Specific Clones Diverse Repertoire Of B cells and T cell CTL Memory Cells Process of Expansion and Differentiation takes time which is why AdaptiveImmunity is Delayed

  14. Lytic granules Containing Granzyme B CD8+ CTL Lysis of infected Cells IL-2 IFNg APC APC IL-4 IL-12 ? Filaria LPS/TLR4 IFNg IL-4, 5, 6, 10 TH2 TH1 B cells B cells IgG2a Viral and Bacterial infections IgG, IgE Extracellular Helminthic Infections What determines unique Thelper differentiation? PAMPS / APC CD4+ T helper IL-2

  15. Activated APC Leave eye Carrying Pathogenic Molecules Blood Stream Afferent Lymphatics Efferent Lymphatics Lymph Node Infections Activate Innate Immunity via PAMPS T and B cell expansion And differentiation occur

  16. 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

  17. Antibody Mediated Cell lysis via Antibody Dependent Cellular Cytotoxicity Rh Hemolytic anemia in newborns Sympathetic ophthalmia, Uveitis Comp MAC Phagocytosis What is Type II Hypersensitivity?

  18. 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 III Hypersensitivity?

  19. 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 IV Hypersensitivity?

  20. Antibodies are generated which are stimulatory Graves Disease Anti-thyroid stimulating hormone receptor antibodies stimulate the effects of Thyroid Stimulating Hormone Antibody TSH TSHR What is Type V Hypersensitivity?

  21. 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

  22. 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

  23. 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

  24. Three Signals are Required for Full T cell activation • TCR : MHC/peptide • Costimulatory Molecules • Cytokine Production 3 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

  25. 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?)

  26. 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

  27. Anatomical Barriers to Host Immune Response Cornea is avascular Interior of Eye lacks demonstrable lymphatic drainage Blood Aqueous Barrier Blood Retinal Barrier

  28. 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

  29. 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+

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