Autoimmunity, Autoinflammation, and Infection in Uveitis

Purpose: To review the pathogenesis of uveitis in light of recent advances in our understanding of innate and adaptive immune responses and their regulation. Design: Perspective. Methods: Methods included a review of prevailing views on the pathogenesis of uveitis and an analysis of developments in immunology that impact on its conceptual basis, particularly the concept of immunologic tolerance and its loss in autoimmunity. Importantly, the role of infection in the pathogenesis of uveitis is evaluated. Results: The results comprise a reappraisal of the pathogenesis of anterior vs posterior uveitis in the context of the blood-retinal barrier and its relation to autoimmune, autoinflammatory, and infectious uveitis. Autoimmunity is seen as a possible cause of certain forms of uveitis but definitive proof is lacking. Autoinflammatory disease, involving activated innate immune mechanisms, is considered causative in a second set of uveitis conditions. A place for infection in uveitis generally is proposed within a unifying concept for the pathogenesis of uveitis. Conclusion: Infection may be implicated directly or indirectly in many forms of noninfectious or undifferentiated uveitis. In addition to the growing recognition that foreign antigen, including reactivatable infectious agents, might hide within ocular tissues, the possibility that a dysregulated microbiome might generate T cells that cause immune-mediated ocular inflammation has now been demonstrated experimentally. An uncontrolled, overexuberant host immune response may cause continuing irreversible tissue damage even after the infection has been cleared.