Immune Mediators in Birdshot Chorioretinopathy: A Systematic Review

PURPOSE: Birdshot chorioretinopathy (BSCR) is a rare, chronic, bilateral posterior uveitis uniquely associated with HLA-A29. Despite this genetic linkage, the immune mechanisms driving BSCR remain poorly defined. We conducted a systematic review to synthesize evidence on immune mediators in BSCR and their potential as biomarkers or therapeutic targets. METHODS: Canada a systematic search of OVID MEDLINE, PubMed and Embase databases was performed on August 1, 2024 following PRISMA guidelines. Eligible studies investigated cytokines, chemokines, and immune cell populations in BSCR. Non-English studies, animal models, and reviews were excluded. Data extraction and risk-of-bias assessments were independently completed by two reviewers. RESULTS: Of the 130 screened studies, 14 met inclusion criteria. Samples from peripheral blood, aqueous humor, and vitreous humor were evaluated using enzyme-linked immunosorbent assay, flow cytometry, and RNA sequencing. Th17-associated signaling was implicated, with elevated intraocular IL-17 and systemic IL-21, IL-23, TGF-β that responded to treatment. Elevated intraocular IL-6, TNF, IP-10, MCP-1, and soluble adhesion molecules supported localized inflammation. Cellular studies showed consistent elevation of Th17 cells in the blood and CD8+ T-cells in the vitreous. Single-cell RNA sequencing revealed treatment-responsive expansion of pro-inflammatory natural killer (NK) cells. B-cells and T-regulatory cells showed minimal or inconsistent alterations. CONCLUSION: BSCR pathogenesis involves a Th17-mediated inflammatory response, with CD8+ and NK cell involvement. While anti-TNF agents remain an established treatment for refractory BSCR, the clinical failure of IL-17A inhibitors suggests that broader inhibition, such as dual IL-17A/F blockade, may be needed. Future studies integrating single-cell techniques and tissue-specific insights are needed to understand disease mechanism and guide treatment.