Viral triggers and genetic predisposition in ocular autoimmunity: unraveling the breakdown of immune privilege and advancing targeted therapeutics.

The eye maintains vision through a distinctive immune privilege, utilizing physical barriers and active immunosuppression mediated by molecules such as FasL and PD-L1, as well as cells, including regulatory T cells and RPE cells. The emergence of sight-threatening immune-mediated ocular diseases, including non-infectious uveitis, signifies a significant disruption of this tolerance. This review analyzes the role of viral triggers and genetic predisposition in inducing immunological failure, while emphasizing the development of targeted therapeutic strategies. Viruses induce autoimmunity through molecular mimicry (Rotavirus peptides cross-reacting with retinal S-antigen), bystander activation, and active immune suppression (CMV inhibiting RPE cell IDO1 activity). HLA alleles, especially HLA-A29 (Birdshot Chorioretinopathy) and HLA-B27 (acute anterior uveitis), as well as non-MHC genes like NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and AIRE, greatly increase the risk of genetic disorders. Treatment is progressing towards precision medicine, with targeted biologics like the IL-6 receptor inhibitor Tocilizumab being key strategies. Moreover, AAV-mediated gene therapy that expresses immunosuppressive molecules such as HLA-G demonstrates promise for the restoration of long-term tolerance in preclinical models, facilitating the development of advanced future strategies.