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Introduction to Immunology of the Eye Nonself Self Other people’s cells Material from other life forms Worms Dangerous Self and Commensal Nonself NON-SELF SELF Dangerous Not Dangerous Two Theaters of the Immune System Humoral: Target is Outside the Cell A soluble protein or other molecule that interacts with a cell free Nonself molecule or organism and neutralizes or eliminated the bound item. Examples: Antibodies and Compliment Cell Mediated: Target is Inside the Cell or the cell itself Immune cell interacts with other cells, and destroys or alters the function of that cell Examples: CD8 T cell, NK Cells, Gamma Delta T cells Innate Receptors How the Immune System Recognizes Nonself and Danger • • • • • Ancient: Found in worms and flies Recognize molecular motifs common to microbes Encoded in your Germline DNA Expressed throughout the body Toll-like Receptors (TLR) are the “Flagship” Innate immune receptor • TLRs are expressed on the corneal epithelium Adaptive Receptors – (Mucosal Immunology (2015) 8, 1000–1008) TLR: Germline Receptors that recognize Pathogen Associated Molecular Patterns Adaptive Receptors Innate Receptors How the Immune System Recognize Non-self and Danger • • • • • • Ancient: Found in worms and flies Recognize molecular motifs common to microbes Encoded in your Germline DNA Expressed throughout the body Toll-like Receptors (TLR) are the “Flagship” Innate immune receptor TLRs are expressed on the corneal epithelium – (Mucosal Immunology (2015) 8, 1000–1008) • • • Found in vertebrates Expressed only in specialized immune cells Generated through recombination of the DNA in specialized immune cells – – • • • B cells T cells Receptor Specificity is Random Molecular Targets/Ligands are referred to as “Antigens” The B and T cell populations needs to be “educated” and activated in order to respond to Antigen Adaptive Immune Receptors: RAG Generate Receptors The Adaptive Immune Response: Clonal Expansion and Selection is a microcosm of natural selection The Immune System Adaptive Innate Humoral Cell Mediated Natural Killer Cells Complement The branches of the immune system interact and overlap Cell Mediated Adaptive Humoral Innate Immunology of the Eye Innate Humoral The Tear Film • Tear film has antiseptic properties • Tear Film Contains Amylases, Peroxidases, Lysozyme • Defensins are small, 29-45aa, proteins – α-defensins: released by immune effector cells – β-defensins: expressed by epithelial cells – θ-defensins: these exist, at least in non-human primates • They have intrinsic anti-microbial properties • Defensins in the tear film – α-defensins: found in the tear film after insult: infection or transplant – β-defensins: constituently present in the eye and in response to infection of the cornea β-defensins • hBD-1 constitutively expressed in the eye • hBD-2 is upregulated in corneal epithelial cells following exposure to PAMPs • hBD-3 fits both parameters • Mutations in Defensins have been shown to increase replication of bacteria on corneal surface Ocul Surf. 2004 Oct; 2(4): 229–247. Corneas of Beta-Defensin KO mice (Left) and WT (right)4.5 h after inoculation P. aeruginosa strain PAO1-GFP (green). Danielle K. Augustin et al. Infect. Immun. 2011;79:595-605 Immunology of the Eye <12 hrs post-Insult Innate Cell Mediated: Attracting Immune Cells • TLR ligation can activate corneal resident immune cells-dendritic cells • TLR ligation of dendritic cells and the corneal epithelium induces chemokine expression • Chemokines are soluble molecules that attract cells • CXCL1 (KC): Attracts Neutrophils • CXCL2 (MIP-2): Attracts Macrophages and Neutrophils Dendritic Cells Surface Markers CD11b CD11c MHC II CD8alpha Neutrophil Surface Marker: CD11bHI Gr-1HI Ly6C lo ly6Ghi Macrophage Surface Markers: CD11b F4/80 MHC II ViralNeutrophils Replicationand in the Macrophages Cornea TwoCan Days Not After Directly Target HSV-1 theInfection Virally Infected Cell Neutrophils and Macrophage Migrate into the cornea within 24hrs • Non-specific tissue damage through the release of reactive oxygen species • Phagocytosis of dead, dying or stressed cells • Release of more Chemokines and Cytokines Innate Cell Mediated: Attracting More Immune Cells • TLR ligation of cells in the corneal epithelium induces chemokine expression • Chemokines are soluble molecules that attract cells • CXCL1 (KC): Attracts Neutrophils • CXCL2 (MIP-2): Attracts Macrophages and Neutrophils • CCL5: Attracts NK cells • CXCL10: Attracts NK cells NK Cells • Express lytic granules • NK are always ready to kill • Decision to kill is result of integration of activation Receptors and Inhibitory Receptors Signals Surface Markers CD56 (humans) CD16 (humans) DX5 (mice and humans) NKp46 (mouse) NK1.1 (C57BL/6 mice) The Lytic Hit Cornea 4 days After HSV-1 Infection 4000 3000 2000 1000 te B d S 0 N K D e p le P pfu/cornea • Lytic Granule: Low pH to keep enzymes inactive • Release into a extracellular space between the target cell and NK cells • Granzyme A: enter the nuclease and activates DNA repair machinery • Granzyme B: Acts on the mitochondria to induce the release of cytochrome C and induce Apoptosis • Perforin: Pore forming protein necessary for granzyme entry into the cell Immunology of the Eye 48 hrs post-Insult Dendritic Cells Junction between Innate and Adaptive Immune Response Dendritic Cells Surface Markers CD11b Corneal Dendritic Cells CD11c -PROFESSIONAL ANTIGEN PRESENTING CELLS MHC II -Activated During Infection CD8alpha -Produce Chemokines -Travel to the Draining lymph node Dendritic Cells Junction between Innate and Adaptive Immune Response • Both Macrophage and Dendritic Cells are “Professional Antigen Presenting Cells” APCs • Both will take up Antigen • Both will present antigen to T cells • Dendritic cells will leave the cornea Professional APCs and T cells • T cells can only interact with Antigen when it is loaded into a MHC molecule • Two Types of T cells – CD8+: Killer T cells – CD4+: Helper T cells • CD8 Cells Interact MHC Class 1 • CD4 Cells Interact MHC Class 2 • MHC 1 expressed by every cell • MHC 2 expressed only by APCs Adaptive Cell Mediate Immunity • Dendritic Cells Express Both MHC 1 and MHC 2 • Activated Dendritic cells express Co-stimulatory molecules – B7 Family (CD86, CD80) and TNFR Family(OX40L, CD70) • Naïve T cells that encounter antigen without co-stimulation will not become effector cells Dendritic Cells Take Antigen Out of the Cornea in Search of T cells (>48hrs) • Depletion of Corneal Dendritic Cells Prior to HSV-1 infection is lethal • Antigen Can Also Drain From the Cornea Independent of DCs • Primed T cells Return to the Cornea (7 days post-insult) Priming of B cells • B cells are Present in the Draining Lymph Node • B Cells Bind Extra Cellular Antigens • Strong Ligation of the BCR will lead to B-cell proliferation • Strong Ligation of the BCR will lead to production of IgM B cell Antibodies: Adaptive Humoral Immunity Antigen Binding (Variable) Region Constant Region IgA is necessary for adaptive humoral immunity in the eye Priming of B cells B cell • B cells are Present in the Draining Lymph Node • B Cells Bind Extra Cellular Antigens • Strong Ligation of the BCR will lead to B-cell proliferation • Strong Ligation of the BCR will lead to production of IgM • B cells require CD4 help for antibody class switching CD4 T cell are required for Antibody class switching • Typically, antigen alone is not enough to prime a B cell response • CD40L expressed by CD4 cells is necessary for B cell class switching and survival • The cytokines produced by the CD4 cells direct antibody class switching CD4 T cells are required for Antibody Class Switching (7-14 days post-insult) The eye maintains it own plasma cell population (>14 days post-insult) • IgA Plasma Cells are resident in Lamina Propria/lacrimal gland • This allows antibody transfer to tear film and ocular surface • Deficiencies in IgA , class switching or CD4 T cells leads to chronic conjunctivitis • <12 hrs tears film destroys bacteria • >12 hrs PAMP driven Inflammation leads to increase chemokine production • <24 hrs Neutrophils and immature Macrophages enter the cornea • 24-48 hrs Macrophages and Dendritic cells mature • 48 hrs NK cells enter the cornea • >48 hrs Dendritic cells travel to the DLN • 3-7 days Dendritic Cells Prime the T cell responses • 7 days T cells travel to cornea • 7 days IgM production • >7 days B cells class switching • >14 days Plasma Cells become resident in the lacrimal gland • Infiltrate will shrink • IgA will be present in tear film Allergies • There are 4 types of allergic responses • The common rapid allergic response that causes itchy eyes and air way stress is Type 1 • Type 1 is mediated by IgE responses Type 1 Allergies are mediated by innate cells armed with adaptive molecules • Mast cells and Eosinophils are granulocytes • They express FC receptors with a high affinity for IgE • These innate cells become armed with adaptive receptors • IgE ligation cause rapid degranulation • Common therapeutics in eyed drops are mast cell stabilizers (cromolyn) The choice between IgE or IgG is control CD4 T cell subtypes ILC (innate Lymphoid Cells) Regulate the Innate Response • ILCs are present in tissue • Respond to alarmins – IL-25 – IL-33 • Based on the alarmin ratios ILCs will differentiate into ILC subtypes • IL-33 is constitutively expressed in cornea epithelium and most mucosal tissue