Inherited retinal disease-associated uveitis

Abstract

Inherited retinal diseases (IRDs) are genetic disorders characterized by progressive photoreceptor function loss, often leading to significant visual impairment. Uveitis has been increasingly recognized in the clinical course of some IRDs. Despite advances in understanding the genetic causes and pathophysiology of IRDs, gaps remain in understanding the roles of inflammation and autoimmunity in IRD and IRD-associated uveitis. This review discusses IRD-associated uveitis, including anterior, intermediate, posterior, and panuveitis, as well as complications such as cystoid macular edema and retinal vasculitis. In patients with IRD-associated uveitis, mutations affecting protein function in cilia or photoreceptor outer segments suggest a universal autoimmune mechanism triggered by the immunogenicity of shedding photoreceptor discs. Notably, in patients where uveitis is the initial sign, CRB1 mutations are often implicated, likely due to the compromised blood-retina barrier function or alterations in the external limiting membrane. Other mechanisms leading to uveitis preceding IRD diagnosis include ALPK1 mutations, which activate the proinflammatory NF-κB pathway, CAPN5 mutations, which lead to dysfunction of the innate and adaptive immune systems, and VCAN1 mutations, which elicit immunogenicity due to irregularities in vitreous modeling. Understanding these mechanisms could enhance the development of innovative treatments that target personalized inflammation pathways in IRDs. © 2025 Elsevier Inc.