The Immunopathogenesis of Uveitis

Abstract

Uveitis encompasses a heterogeneous group of intraocular inflammatory disorders and remains a leading cause of preventable visual loss. Its immunopathogenesis reflects the interplay between a uniquely regulated ocular environment and triggers that breach or bypass that privilege. Much of our mechanistic understanding derives from animal models, which have helped define key features of ocular immune regulation. Layered mechanisms normally restrain inflammation: physical barriers (blood–aqueous and blood–retina), a locally immunosuppressive milieu, and systemic tolerance circuits such as anterior chamber–associated immune deviation. When these controls fail, disease emerges through three broad pathways. In autoimmune uveitis, genetic susceptibility (HLA class I/II and peptide-trimming enzymes such as ERAP) shapes antigen display and lowers activation thresholds for autoreactive T cells. Antigen presentation in draining nodes primes Th1/Th17 responses. Within the eye, effector T cells are restimulated by resident microglia and recruited macrophages, driving cytokine cascades that disrupt the blood–retina barrier and amplify leukocyte recruitment. B cells may augment tissue injury via antigen presentation, cytokine production, local antibody formation, and, in some entities, ectopic lymphoid structures. These mechanisms are largely defined in experimental autoimmune uveitis and form the basis for extrapolating human pathogenesis. Tissue-resident memory T cells persist into remission and may influence relapse risk. Autoinflammatory uveitis arises from dysregulated innate pathways independent of antigen specificity. Infectious uveitis reflects direct intraocular infection or reactivation. Post-infectious inflammation may be sustained by antigen persistence or molecular mimicry. Paraneoplastic uveitis (autoimmune retinopathy) arises when anti-tumour immunity cross-reacts with retinal antigens. Therapy should mirror the dominant immunopathology. In infectious uveitis, clinicians first reduce pathogen load with targeted antimicrobials and then add anti-inflammatory therapy under antimicrobial cover; maintenance antivirals curb reactivation when indicated. In autoimmune disease, where Th1/Th17–macrophage circuits dominate, steroid-sparing treatment targets TNF and IL-6 pathways. In autoinflammatory forms, excess inflammasome/IL-1 signalling supports IL-1 blockade. Advances in humanised modelling will be key to defining condition-specific mechanisms and supporting the evolution of tailored interventions.