Ocular Immunology In Depth: Immune Privilege, Hypersensitivity, HLA and Immunosuppression
Last updated: November 2026
Uveitis, allergy, graft rejection, macular degeneration and even herpes keratitis are, at heart, immunological diseases. This in-depth guide explains the immune system in the eye, how its privilege works and fails, and how the drugs we use act on it.
Immune system basics
| Arm | Components | Features |
|---|---|---|
| Innate | Barriers, neutrophils, macrophages, NK cells, mast cells, complement, toll-like receptors | Fast, non-specific, no memory |
| Adaptive | T cells (CD4 helper: Th1, Th2, Th17, regulatory; CD8 cytotoxic) and B cells (antibodies) | Specific, slower first time, memory |
- MHC class I (all nucleated cells) presents to CD8 cells; class II (antigen-presenting cells such as dendritic cells and macrophages) presents to CD4 cells.
- Th1 (IFN-γ) and Th17 (IL-17, driven by IL-23) cells drive most non-infectious uveitis; Th2 (IL-4, IL-5, IL-13) cells drive allergy.
- Key cytokines and their drugs: TNF-α (adalimumab, infliximab), IL-6 (tocilizumab), IL-17 and IL-23 (under study), IL-2 pathway (ciclosporin, tacrolimus).
Immunity of the ocular surface
- Tear proteins: lysozyme, lactoferrin, lipocalin, defensins, secretory IgA (the main tear antibody).
- Conjunctiva-associated lymphoid tissue (CALT) samples antigens; goblet cell mucins trap microbes.
- The corneal epithelium and its tight junctions are a strong barrier; Langerhans cells (antigen-presenting) are found mostly in the peripheral cornea and migrate centrally with inflammation.
- Commensal bacteria compete with pathogens; long-term antibiotics disturb this balance.
Immune privilege
| Mechanism | Effect |
|---|---|
| Blood-ocular barriers and lack of lymphatics (cornea, inner eye) | Limit entry of cells and antigen leaving to lymph nodes |
| Immunosuppressive aqueous (TGF-β2, alpha-MSH, VIP, CGRP) | Suppresses T cell activation and complement |
| Fas ligand and PD-L1 on ocular cells | Trigger death or inactivation of invading activated T cells |
| Low MHC class II expression in the cornea and retina | Reduces antigen presentation |
| ACAID (anterior chamber-associated immune deviation) | Antigen in the anterior chamber induces regulatory T cells and systemic suppression of delayed hypersensitivity, via the spleen |
Privilege is relative: inflammation, vascularisation and trauma break it down, as in corneal graft rejection or sympathetic ophthalmia.
Hypersensitivity in the eye
| Type | Mechanism | Ocular examples |
|---|---|---|
| I: immediate (IgE) | Mast cell degranulation: histamine, leukotrienes; eosinophils in the late phase | Seasonal allergic conjunctivitis, VKC and AKC (with type IV components), anaphylactic lid swelling |
| II: antibody-mediated cytotoxic | IgG or IgA against tissue antigens, complement | Mucous membrane (ocular cicatricial) pemphigoid (antibodies to basement membrane proteins), myasthenia gravis (acetylcholine receptor antibodies) |
| III: immune complex | Complexes deposit in vessels, complement, neutrophils | Scleritis and peripheral ulcerative keratitis in rheumatoid arthritis and vasculitis, marginal keratitis (staphylococcal), Wessely immune ring, retinal vasculitis in SLE |
| IV: delayed (T cell) | Sensitised T cells and macrophages | Phlyctenulosis, contact dermatitis to drops, corneal graft rejection, sympathetic ophthalmia, granulomatous uveitis, herpetic stromal keratitis, tuberculin reaction |
Autoimmunity and uveitis
- Experimental autoimmune uveitis is induced by retinal antigens such as S-antigen (arrestin) and interphotoreceptor retinoid-binding protein (IRBP): the model for sympathetic ophthalmia and VKH.
- VKH and sympathetic ophthalmia involve T cell responses to melanocyte antigens (tyrosinase family), explaining vitiligo, poliosis and hearing loss.
- HLA-B27 acute anterior uveitis links to gut microbiota and spondyloarthritis.
- Immune checkpoint inhibitors for cancer (anti-PD-1, anti-CTLA-4) can cause uveitis, including VKH-like disease, and myasthenia.
HLA associations
| HLA | Association |
|---|---|
| HLA-B27 | Acute anterior uveitis, ankylosing spondylitis, reactive arthritis, psoriatic and IBD arthritis |
| HLA-A29 | Birdshot chorioretinopathy (over 95%) |
| HLA-B51 | Behçet disease |
| HLA-DR4 (DRB1*04:05) | VKH, sympathetic ophthalmia |
| HLA-DR15 (DR2) | Intermediate uveitis with multiple sclerosis |
| HLA-B7, DR2 | Presumed ocular histoplasmosis |
| HLA-B*15:02 | Carbamazepine-induced Stevens-Johnson syndrome in people of South-East Asian ancestry (pre-treatment screening is advised in some populations) |
| HLA-DR3, DR4 | Thyroid eye disease (weak), type 1 diabetes |
Complement and AMD
- Complement factor H (CFH Y402H) and other complement gene variants are the strongest genetic risk factors for AMD.
- Drusen contain complement components; chronic complement activation drives RPE and photoreceptor loss in geographic atrophy.
- New drugs inhibit complement: pegcetacoplan (C3) and avacincaptad pegol (C5) slow GA growth. See GA treatment.
Infection and immunity
- Herpes simplex: latent in the trigeminal ganglion; epithelial keratitis is viral replication, stromal keratitis is mostly immune-mediated (hence steroids under antiviral cover, HEDS).
- Toxoplasma: tissue cysts reactivate when local immunity falls; immunosuppressed patients get atypical, severe disease.
- CMV retinitis needs profound immunosuppression (CD4 below 50); immune recovery uveitis follows immune reconstitution.
- Endophthalmitis: inflammation itself destroys the retina, so early antibiotics (and sometimes steroids) matter.
Corneal graft rejection
| Type | Signs | Treatment |
|---|---|---|
| Epithelial | Raised epithelial rejection line | Topical steroid |
| Subepithelial | Krachmer spots (subepithelial infiltrates) | Topical steroid |
| Stromal | Stromal haze and vessels | Intensive steroid |
| Endothelial | Khodadoust line (KPs advancing across the endothelium with oedema behind), diffuse KPs; the most serious | Hourly topical steroid, plus systemic or periocular steroid |
- High-risk grafts: vascularised beds, previous rejection, inflamed or infected eyes, large or eccentric grafts, children, regrafts. Lamellar grafts (DALK, DMEK) have lower rejection rates than penetrating keratoplasty.
Immunosuppressive and immunomodulatory drugs
| Drug | Mechanism | Key monitoring and cautions |
|---|---|---|
| Corticosteroids | Broad suppression of cytokine genes and leucocyte migration | IOP, cataract, glucose, BP, bones, infection; taper slowly |
| Methotrexate | Antimetabolite (folate antagonist) | Weekly dosing with folic acid; blood count, liver tests; avoid in pregnancy and alcohol |
| Mycophenolate | Inhibits purine synthesis in lymphocytes | Blood count; GI upset; teratogenic |
| Azathioprine | Purine analogue | Check TPMT activity before starting; blood count, liver tests |
| Ciclosporin, tacrolimus | Calcineurin inhibitors (block IL-2) | BP, kidney function, drug interactions; topical forms for VKC and dry eye |
| Cyclophosphamide | Alkylating agent | Severe vasculitis, OCP; bladder toxicity, infertility, malignancy |
| Adalimumab, infliximab | Anti-TNF-α antibodies | Screen for TB and hepatitis B; avoid in demyelinating disease |
| Rituximab | Anti-CD20 (depletes B cells) | ANCA vasculitis, OCP, scleritis; infusion reactions, infection |
| Tocilizumab | Anti-IL-6 receptor | GCA, refractory uveitis and TED |
| Teprotumumab | Anti-IGF-1 receptor | Thyroid eye disease; hearing loss, hyperglycaemia |
Where residents slip
- Calling OCP a type I reaction (it is antibody-mediated, type II).
- Starting anti-TNF without screening for TB and hepatitis B.
- Forgetting TPMT before azathioprine.
- Treating herpetic stromal keratitis with antivirals alone (it is mostly immune-mediated).
- Missing the Khodadoust line in a red, hazy graft.
Test yourself: flip cards
Quick quiz
Related: Uveitis Made Easy: SUN Terms, Patterns and Work-up, Keratoplasty Types: PK vs DALK vs DSAEK vs DMEK, Allergic Conjunctivitis and VKC: Types, Grading and Steroid-Sparing Treatment, Revise ophthalmology checklist.
Key sources
- Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3:879-889
- American Academy of Ophthalmology. BCSC Section 9: Uveitis and Ocular Inflammation (current edition)
- Jabs DA, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders. Am J Ophthalmol. 2000;130:492-513
- Forrester JV, et al. The Eye: Basic Sciences in Practice. 5th ed. Elsevier; 2020
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