Ocular Immune System PDF

**Unit 2 Part 2 -- Ocular Immune System** - Eye maintains immune privilege: evolutionary adaptation to minimise the immune system when a pathogen enter to protect the eyes - Sites of immune privilege: 1. Cornea 2. Anterior Chamber - Factors contributing to immune privilege in the ey...

**Unit 2 Part 2 -- Ocular Immune System** - Eye maintains immune privilege: evolutionary adaptation to minimise the immune system when a pathogen enter to protect the eyes - Sites of immune privilege: 1. Cornea 2. Anterior Chamber - Factors contributing to immune privilege in the eye +-----------------------------------+-----------------------------------+ | BLOOD OCULAR BARRIER | - **Zonula occluden junctions** | | | (keeps fluids AH + vitreous | | | sep from blood) | | | | | | - Between endothelial cells | | | in blood vessels of the | | | iris + retina (ENDORI) | | | | | | - Between epithelial cells | | | of the ciliary body + | | | retina (EPIC) | | | | | | - Barriers restrict blood-borne | | | molecules + cells that | | | participate in innate + | | | adaptive immunity from | | | entering the eye | +===================================+===================================+ | Absence of lymphatic vessels | - No patent lymphatic vessels | | | have been demonstrated in AC, | | | Vitreous or Retina in mammals | | | | | | - AH drains into the venous | | | system instead of the | | | lymphatic system | | | | | | - Antigens + APCs travel to the | | | SPLEEN in the blood stream | | | | | | - Spleen rather than regional | | | lymph nodes provides the | | | primary site for the initial | | | immune response to | | | intraocular antigens | +-----------------------------------+-----------------------------------+ | Cells lining the anterior chamber | - Anterior Chamber Associated | | and subretinal space synthesise | Immune Deviation: | | substances + actively contribute | | | to immunosuppressive | Cells produce substances that | | microenvironment | suppress the immune system | +-----------------------------------+-----------------------------------+ - Cornea + conjunctiva: constantly under attack from foreign substances 1. Tears: irrigation removes the microbes 2. Blinking 3. Temperature of the cornea: doesn't allow the microbe to survive 4. Intact epithelial surface prevents the influx of pathogens into the eye **[TEAR FILM]**: Contributes in four different ways: 1. Mechanical barrier -- tear film + mucin glycoproteins (produced from goblet cells) trap micro-organisms 2. Regular washing of tears + blinking removes the microbed 3. Polymorphonuclear Leuckocytes 4. Tear film contains many antibacterial proteins: +-----------------------------------+-----------------------------------+ | Ceruloplasmin | - Free radical removal | +===================================+===================================+ | Complement | - Complement cascade -- 9 | | | proteins which leads to cell | | | lysis | +-----------------------------------+-----------------------------------+ | sIgA | - Secreted antibody | | | | | | - Present in normal eyes | | | | | | - Neutralises viruses | | | | | | - Inhibits bacterial adherence | | | to ocular surface epithelium | +-----------------------------------+-----------------------------------+ | IgE | - Normal levels very low | | | | | | - Increased in allergic | | | responses | +-----------------------------------+-----------------------------------+ | IgG | - Antigen specific antibody | | | | | | - Only present in pathological | | | circumstances | +-----------------------------------+-----------------------------------+ | Lysozyme | - Proteolytic enzyme | | | | | | - In the presence of | | | complement, facilitates IgA | | | bacteriolysis | +-----------------------------------+-----------------------------------+ | Lactoferrin | - Chelation of iron + | | | destabilisation of bacterial | | | membranes (bacteriostatic) | | | | | | - Needed for the working of | | | lysozyme | | | | | | - Role in free radical removal | +-----------------------------------+-----------------------------------+ | Transferrin | - Iron chelator | | | | | | - Anti-oxidant effect | +-----------------------------------+-----------------------------------+ Conjunctival Immune system = Conjunctival MALT Main players of Conjunctival MALT - Langherans cells: phagocytose the infectious/non-infectious antigens and present them on its surface in draining lymph nodes to activate other immune cells - Lateral conjunctiva -- drains to periauricular lymph nodes - Nasal conjunctiva -- drains to submental lymph nodes - B cell -- present in the subepithelial layer - T cell -- present in the subepithelial layer - Mast cells, PMNs, eosinophils also present in the subepithelial layer - In chronic infections the lymphocytes can aggregate to form follicular conjunctivitis **[BLEPHARITIS]**: Chronic condition - **T -cells** main immune cell - Antigen is unaware but could be linked to bacteria -- e.g. staphylococci **[CICATRICAL PEMPHIGOID MEMBRANE: ]** - Scarring + cicatrisation - Symblepharon - Can be assoc with scarring in the mouth - Linear deposition of antibodies to the basement membrane zone - A**cute disease: macrophages, neutrophils, T cells (helper + cytotoxic), few B cells** **[ALLERGIC CONUNCTIVITIS]**: - Type 1 hypersensitivity reactions -- acute allergy - Seasonal -- allergen in pollen - Perennial -- allergen is house dust mites - Atopic asthma, eczema, allergic rhinitis - Can also have allergic reactions to preservative in eye drops - **[ACUTE ALLERGY]**: - Influx of **mast cells + eosinophils** - IgE with mast cells binds to allergen - Histamine released - **[CHRONIC ALLERGIC CONJUNCTIVITS]**: - Giant papillary conjunctivitis, Vernal keratoconjunctivitis, Atopic keratoconjunctivitis - Mast cells + eosinophils + T cell response - **[TH1 response]**: VKC + GPC - **[TH2 response (IL-2 + IFN- gamma)]**: AKC -AKC px are at risk of herpetic corneal infection which may be bilateral -VKC+AKC: both may need topical steroids, can also use topical cyclosporins which reduce the amount of cytokines produced by T cells -GPC not associated with atopy -- more with cls or ocular prosthesis **[Pterygium]**: - Commonly seen in hot countries - Now thought that immune mechanisms may be involved in pterygium formation as opposed to pinguecula - Class 2 MHC molecule HLA-DR (involved in antigen presentation) abundantly expressed in pterygium epithelial cells whereas no expression found in pinguecula - **Ki-67 + PCNA** expression in same areas as HLA-DR antigen expression in pterygium + increased number of inflammatory cells **[Cornea]**: -main defence comes from surrounding limbus + anterior chamber -limbus contains lymphocytes + Langerhans Cells: rarely found in the normal cornea but increasing quantities in infectious and non-infectious quantities -**Mooren's ulcer** + **Terrien's Marginal degeneration**: non-infectious disorder -- occurs adjacent to the limbus -**Wegener's Granulomatosis** + **Acne Rosacae**: cornea + nearby sclera involved -Herpes Simplex -- involves the corneal epithelium but sometimes an immune response can occur and involve the underlying stroma -- leading to uveitis -Herpes Zoster -- can also cause uveitis -Nummular keratitis -- needs topical steroids CORNEAL TRANSPLANTATION SUCCESS RATE: 90% - Due to cornea being avascular and has a lack of immune activation - Success rate is reduced in immunocompromised pxs/neovascularisation of cornea/peripheral anterior synechiae - Reducing chances of corneal graft rejection: 1. Immunosuppressive therapy: cyclosporin + mycophenolate (needs to be used for a year) 2. HLA matching of donor + recipient particularly of DR subtypes - **[GRAFT REJECTION]**: topical steroids + possibly systemic corticosteroid therapy **[IMMUNOLOGY OF THE SCLERA]**: - Sclera: mainly composed of collagen fibres, in contrast to the cornea -- sclera is opaque and covered by a sheet of episclera - **[Main inflammatory cells]**: 1. T-cells -- predominance of T-helper cells -- express IL-2 2. Macrophages 3. Clusters of B cells: found in perivascular areas 4. Neutrophils 5. Macrophages 6. Plasma cells **[IMMUNOLOGY OF THE UVEA]**: - IRIS + CILIARY BODY + CHOROID - Highly vascularised tissues - Do NOT contain lymph vessels + process no draining lymph nodes - Low iris blood vessel permeability + tight junctions: maintain BAB + BRB - BAB: tight junctions between non-pigmented ciliary epithelial - BRB: tight junctions between RPE cells - PATHOLOGICAL CONDITIONS: alters the barriers and allows leukocyte migration + increased vascular permeability **[ACUTE UVEITIS]**: - Influx of PMNs + T-cells into the anterior chamber - 60% of these pxs are HLA B27 positive - HLA B27 negative -- can also have a similar response - Chronic uveitis -- not generally HLA B27 positive -- more assoc with other disorders: sarcoidosis - Increased levels of IL-10: inflammation down-regulatory cytokine (may be seen in less aggressive forms of inflammation such as Fuch's Heterochromic Cyclitis) **[POSTERIOR UVEITIS]**: - Uvea is in close contact with the retina + scleral tissue -- inflammation can also occur in the retina + scleral tissue - Many different causes of posterior uveitis: -systemic diseases (sarcoidosis + Behcet's disease) -CD4+ T cells: produce a variety of cytokines, activated macrophages + HLA DR upregulation -CD8+ T cells -B cells -little evidence to support immune complex deposition as a major cause of inflammation -nature of antigen is not known: retinal s-antigen + interphotoreceptor binding protein -- in animal models of uveitis -VKH -immune response tends to be assoc with melanin assoc antigens - **[Sympathetic ophthalmia]**: -penetrating trauma: includes intraocular surgery in one eye -immune response in one eye initiated -- inflammation occurs bilaterally -predominant: CD4+ with some CD8+ **[IMMUNOLOGY OF THE NEURORETINA + RPE]**: - ANTIGENS: retinal s-antigen, interphotoreceptor retinol binding protein, rhodopsin - Unclear whether these proteins act as immunological targets in the human - MELANOMA-ASSOCIATED RETINOPATHY - CARCINOMA-ASSOCIATED RETINOPATHY -Circulating antibodies to tumor antigens that cross-react with retinal proteins, leading to visual dysfunction - **RETINITIS PIGMENTOSA**: -inlflammatory response may be seen due to retinal antigen sensitisation - **LASER PHOTOCOAGULATION OF ISCHAEMIC RETINA**: -anti-retinal antibodies have been detected -but most likely have no effect on retinal function as they do in CAR + MAR - **AMD**: -Dendritic cell are associated with dreusen development -Complement activation occurs within dreusen + RPE-choroid interface -oxidative stress + free-radical formation + antioxidants: important -IgA, IgG, IgE, C1q, C3c, C3d -- seen in large quantities in surrounding connective tissues + new blood vessels walls -HLA-DR + DQ found in glial, RPE + vascular endothelial cells -Lymphocytes are uncommon **[Immunology of Extra ocular constituents]**: - Optic neuritis: variety of causes, MS, T-cells involved - **[Graves Disease]**: i. EOM's + orbital fat: enlarged + infiltrated by lymphocytes -Predominantly T-cells: CD4+ (both TH1 + TH2), CD8+ present -Glycosaminoglycan production in the muscle fibres which cause them to swell more -Proptosis occurs where there is an increased volume of orbital contents + compression of the optic nerve can occur -damage to EOMs occurs, fibrosis ensues and function is permanently impaired requiring corrective surgery for resulting strabismus - **[Myasthenia Gravis]**: -Weakening of the lid muscles and EOM muscles can occur particularly when the px is tired -Antibodies against the acetylcholine receptor at the synapses exhaust the nerve-muscle transduction - **[Miller Fisher Syndrome]**: -charaterised by a triad of ataxia, ophthalmoplegia + reduced/absent tendon reflexes with minimal if any limb weakness -lymphocytes + macrophages + anti-GQ1B IgG antibodies present in high quantities - **[Lacrimal Gland]**: -autoimmune reaction at lacrimal acinar cells -- which secrete the aqueous component of tears: - Reduces tear volume - Alters composition of tears - Seen in Sjogren Syndrome + Sarcoidosis - T-cell, antibodies + cytokines - Early stages topical cyclosporin has been given to improve tear production -- suggests T cells are involved in the destructive process +-----------------------------------+-----------------------------------+ | DISEASE NAME | IMMUNE CELLS INVOLVED | +===================================+===================================+ | BLEPHARITIS | - T cells | +-----------------------------------+-----------------------------------+ | CIATRICAL PEMPHIGOID | - Macrophages | | | | | | - Neutrophils | | | | | | - T Cell (CD4+ and CD8+) | | | | | | - Few B cells | +-----------------------------------+-----------------------------------+ | ALLERGIC CONJUNCTIVIS | - Mast Cells | | | | | | - Eosinophils | | | | | | - IgE | +-----------------------------------+-----------------------------------+ | CHRONIC ALLERGIC CONJUNCTIVITIS | | +-----------------------------------+-----------------------------------+ | VERNAL KERATOCONJUNCTIVITIS | - Mast Cells | | | | | | - Eosinophilhs | | | | | | - TH2 | +-----------------------------------+-----------------------------------+ | GIANT PAPILLARY CELLS | - Mast Cells | | | | | | - Eosiniphils | | | | | | - TH2 | +-----------------------------------+-----------------------------------+ | ATOPIC KERATOCONJUNCTIVITIS | - Mast Cells | | | | | | - Eosinophils | | | | | | - TH1 | | | | | | - IL-2 | | | | | | - IF-GAMMA | +-----------------------------------+-----------------------------------+ | PTERYGIUM | - HLA-DR | | | | | | - Ki-67 | | | | | | - PCNA expression | +-----------------------------------+-----------------------------------+ | SCLERITIS + EPISCLERITIS | - T-cells (majority CD4+) | | | | | | - Macrophages | | | | | | - IL-2 | +-----------------------------------+-----------------------------------+ | UVEITIS | - HLA B27+ | | | | | | - IL-10 | | | | | | POSTERIOR: | | | | | | - CD4+ | | | | | | - CD8+ | | | | | | - B-Cells | +-----------------------------------+-----------------------------------+ | VKH SYNDROME | - Melanin associated antigens | +-----------------------------------+-----------------------------------+ | SYMPATHETIC OPHTHALMIA + | - CD4+ - predominant | | PENETRATING TRAUMA | | | | - CD8+ | +-----------------------------------+-----------------------------------+ | AMD | - IgA | | | | | | - IgG | | | | | | - IgE | | | | | | - C1q | | | | | | - C3c | | | | | | - C3d | +-----------------------------------+-----------------------------------+