Immune Privilege and the Eye - OPTM2042 2024 PDF

IMMUNE PRIVILEGE AND THE EYE OPTM2042 MECHANISMS OF IMMUNE TOLERANCE IN THE EYE Physical Barriers: The blood-retinal barrier and blood-aqueous barrier limit the access of immune cells and molecules into the eye. These barriers prevent widespread immune activation. Absence of Lymphatic Vesse...

IMMUNE PRIVILEGE AND THE EYE OPTM2042 MECHANISMS OF IMMUNE TOLERANCE IN THE EYE Physical Barriers: The blood-retinal barrier and blood-aqueous barrier limit the access of immune cells and molecules into the eye. These barriers prevent widespread immune activation. Absence of Lymphatic Vessels: The eye has fewer lymphatic vessels, which reduces the flow of antigens to nearby lymph nodes, slowing down immune responses. Local Immunosuppressive Factors: The eye produces various molecules, such as transforming growth factor-beta (TGF-β) and neuropeptides, that suppress inflammation and immune responses. ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION (ACAID) This is a well-studied form of immune tolerance specific to the eye. When antigens (foreign substances) enter the anterior chamber of the eye, they are not met with the typical immune attack. Instead, ACAID promotes a systemic immune response that suppresses aggressive immune actions, leading to tolerance.  Mechanism: Antigens introduced into the anterior chamber are processed by eye-resident antigen-presenting cells, such as macrophages and dendritic cells. These cells travel to the spleen and other immune organs, where they induce T regulatory cells, which dampen immune responses. Role: ACAID helps protect the eye from inflammation and autoimmune attacks that could damage its tissues. It plays a role in maintaining long-term graft survival in corneal transplants. IMMUNE PRIVILEGED SITES The presence of certain sites in the body that can tolerate the introduction of antigen without eliciting an inflammatory immune response As such the immune response is limited or altered to protect tissues from inflammation and damage. Foreign-tissue grafts placed in immune privileged sites are tolerated and survive for indefinite intervals when their placement in conventional body sites leads to acute irreversible immune rejection Thought to be an evolutionary adaptation to protect tissues that are indispensable but have limited regeneration capacity IMMUNE PRIVILEGE First believed to be a suppression of all immune responses Actually it involves selectively downregulating immune responses that will inflict the most injury while preserving the more beneficial components IMMUNE PRIVILEGED SITES Examples include: Eyes: The anterior chamber of the eye has mechanisms to limit immune responses to prevent damage to sensitive tissues. Brain: The central nervous system (CNS) has a unique immune environment, partially due to the blood-brain barrier, which restricts the entry of immune cells and antibodies. Testes: The testes create a barrier to protect sperm from the immune system, which could recognize them as foreign due to their unique antigens. Placenta: The placenta helps to protect the fetus from maternal immune responses, allowing for the development of the embryo without significant immune attack. Bone marrow: This site has limited immune activity to protect hematopoietic stem cells. CHARACTERISTICS Lack of lymphatic drainage – limiting entry of immune cells Low expression of classical MHC Class Ia molecules Expression of immunoregulatory nonclassical, low polymorphic MHC Class Ib molecules Local production of immunosuppressive cytokines e.g. TGF-β Constitutive expression of FasL – controls entry of Fas-expressing lymphoid cells OCULAR IMMUNE SYSTEM THEPHOTO BY PHOTOAUTHOR IS LICENSED UNDER CCYYSA. OCULAR IMMUNE SYSTEM Protects the eye from infection Regulates healing processes Immune cells reside in the uvea Macs, DCs and mast cells Cornea is immunologically important Protects against foreign material and microbial pathogens Prevents injury to the eye THE CORNEA Lack of vasculature and relative immune separation makes immune defense difficult Its most important function is the transmission and refraction of light It does not contain lymphoid cells or other defense mechanisms other than some DCs Many of the immune responses come from other sources e.g. conjunctiva CORNEAL DEFENSIVE MECHANIMS Innate immunity is the first line of defense Physical barriers guard against traumatic events Bony orbit Eyelid Cellular and molecular participants Tears Corneal Nerves Epithelium Keratocytes PMNs Cytokines, Complement system  TEARS Prevent Flush Transport Prevent drying of the cornea Flush foreign particles from the ocular Transport antimicrobial proteins and surface immunoglobulins to the ocular surface Lactoferrin Lysoszyme Lipocalin Beta-lysin Which is the main Ig? TEARS - IMMUNOGLOBULINS Secretory IgA binds to bacteria Prevents bacterial adherence to epithelium Tears' IgG and IgA can neutralise some viruses EPITHELIAL CELLS Presents a physical barrier to prevent microbes from reaching the interior of the eye chamber Capable of secreting cytokines to activate immune defences IL-1α - stored in epithelial cells and keratocytes – passively released when cell membrane is ruptured – encourages leucocyte invasion IL-1αR – soluble and membrane forms – a natural IL-1α antagonist – decreases leucocyte invasion, suppresses neovascularisation  The keratocytes, or corneal fibroblasts, are KERATOCYTES highly specialized cells that are sandwiched between orthogonally arranged layers of collagen lamellae in the corneal stroma. They play a key role in maintaining the structure and transparency of the cornea, as they are the source of stromal collagen and proglycans. Under the influence of IL-1α and TNF-α – synthesis of IL-6 and defensins ▪Defensins : antimicrobial activity, accelerate epithelial healing; also found in neutrophils in conjunctiva ▪Found to secrete IL-8 – attracts neutrophils  Various complement components are in the peripheral and central cornea COMPLEMENT Activation via classical or alternative may be involved in corneal inflammation  CORNEAL DEFENSIVE MECHANISMS Cell-mediated immune Acquired immune responses responses are more efficient are partly controlled by but can cause damage to Langerhans cells in the surround tissue resulting in cornea damage to the vision  Antigen presenting cells of the cornea – a specialised DC Generally found in the periphery of the LANGERHANS cornea CELLS Have been noted in the central cornea of human infants MALT Both innate and adaptive response are incorporated in the network of lymphoid cells that form MALT Lacrimal glands and conjunctiva contribute to ocular defences via secretion of Igs and lymphoid tissue THE EYE http://www.vision-and-eye-health.com/images/Eye-Anatomy-2.jpg Immunopaedia.org IMMUNE PRIVILEGE The eye is considered an immune-privileged site ▪ the immune system's response is somewhat muted compared to other parts of the body. ▪ This immune privilege is critical because inflammation and immune responses in the eye can lead to tissue damage, scarring, and vision loss.  Ocular tissues have minimal ability to regenerate if damaged IMMUNE PRIVILEGED Regulatory systems that limit excessive pro-inflammatory immune SITE – THE responses are present: EYE Barrier systems to restrict Ag and cellular traffic Cell-associated factors that suppress activation & proliferation of leucocytes responding to antigenic stimuli BLOOD-RETINAL BARRIER Retina High susceptibility to damage via inflammatory responses Limited ability to regenerate  Blood-retinal barrier allows segregation of Ags from immune cells in the periphery: Vascular endothelial cells are BLOOD- connected by impermeable tight-junctions RETINAL Bruch’s membrane (basement BARRIER membrane) prevents soluble molecules from diffusing out of the eye https://www.immunopaedia.org.za/immunology/archive/immune-privilege/blood-retina-barrier/tolerance-and-inflammation/sympathetic-ophthalmia/  Retinal pigment epithelium – an BLOOD- impermeable cell layer, RETINAL connected by tight BARRIER junctions Protects the photoreceptor cells https://www.immunopaedia.org.za/immunology/archive/immune-privilege/blood-retina-barrier/tolerance-and-inflammation/sympathetic-ophthalmia/ The eye lacks a lymphatic system that limits detection of ocular Ags However Ags can drain to external lymph nodes through the trabecular network This can elicit an immune response in the peripheral lymph nodes or the spleen Activated immune cells then traffic to the eye TRABECULAR MESHWORK Area of tissue in the eye located around the base of the cornea, near the ciliary body Responsible for draining the aqueous humour from the eye via the anterior chamber  Main goal is to circumvent damage to cells required to maintain vision IMMUNE Lack of expression classical Class Ia HLA-A, - EVASION B and –C receptors CD8+ Tc cells are prevented from responding to foreign peptides  HOWEVER Lack of HLA Class Ia receptor expression activates NK cells to kill IMMUNE EVASION Upregulation of expression of non-classical Class Ib HLA-E and –G receptors These receptors will interact with NK’s CD94/NKG2 receptors Upregulation of expression of non-classical Class Ib HLA-E and –G receptors These receptors will interact with NK’s CD94/NKG2 receptors  Some ocular cells express cell surface APOPTOTIC molecules that trigger FACTORS apoptosis of activated immune cells FasL and PD-L1 engagement promotes apoptosis in activated T cells via Fas and PD-1  Some ocular cells express cell surface molecules that trigger apoptosis of activated immune cells TRAIL engages with Apoptotic TRAIL receptors on macrophages Factors  Some ocular cells express cell surface molecules that trigger apoptosis of activated immune cells FasL and TRAIL engagement promotes apoptosis in Apoptotic neutrophils Factors  Membrane receptors and enzymes that inhibit INHIBITORY proliferation of activated FACTORS immune cells are expressed  CD86 receptors engage the inhibitory receptor CTLA-4 on T cells INHIBITORY FACTORS INHIBITOR CD86 Y FACTORS receptors engage the inhibitory receptor CTLA-4 on T cells INHIBITORY Some ocular cells inhibit T FACTORS cell survival by mediating depletion of Tryptophan using IDO (indolamine 2, 3- dioxygenase) Tryptophan is an essential amino acid required by activated T cells for growth and proliferation ACRONYM ACTUAL SOLUBLE IMMUNOSUPPRESSIVE FUNCTION TGF-β Tumour growth factor- Suppressor of activation of FACTORS beta T, NK cells & Macs Primes APCs to preferentially promote development of Tregs CGRP & α-MSH Calcitonin gene-related Prevents activated Macs protein from secreting pro- Alpha-Melanocyte inflammatory cytokines stimulating hormone  SOLUBLE IMMUNOSUPPRESSIVE FACTORSACTUAL ACRONYM FUNCTION VIP Vasoactive intestinal Suppresses T cell peptide activation SOM Somatostatin Prevents activated T cells from secreting IFN-γ MIF Macrophage migration Inhibits NK cytotoxic inhibitory factor function CRP Complement regulatory Inhibits activation of the proteins complement cascade