EBV-Induced Upregulation of GPR183: A Potential Key Mechanism in the Pathogenesis of IgG4-Related Ophthalmic Disease

Background: Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is the most common subtype of IgG4-related disease (IgG4-RD), yet its upstream pathogenic mechanisms remain elusive. Ectopic germinal centers are among the most characteristic histopathological features of IgG4-ROD, but the molecular drivers promoting their formation are unknown. This study aimed to identify key upstream pathogenic triggers of IgG4-ROD.Methods: We analyzed lacrimal gland biopsy specimens from IgG4-ROD patients and controls using bulk RNA sequencing, multiplex Opal immunofluorescence, and real-time PCR (qPCR).Findings: GPR183 was the only gene consistently upregulated across the lacrimal gland, salivary gland, peripheral blood, and retroperitoneal fibrosis of IgG4-RD patients. Multiplex immunofluorescence revealed GPR183 localization within ectopic germinal centers. qPCR detected significantly higher EBV positive rate in lacrimal glands of IgG4-ROD patients than in controls (92.3% vs 25.0%, P < 0.001). EBV DNA copy numbers in lacrimal glands of IgG4-ROD patients strongly correlated with serum IgG4 levels (R2=0.71, P < 0.001). Multiplex immunofluorescence also revealed that EBV markers namely EBNA1 and LMP1 were co-expressed with GPR183.Interpretation: This study is the first to reveal a link between EBV and IgG4-ROD and to propose a potential mechanism in which EBV induces GPR183 upregulation in the lacrimal gland, promoting the formation of ectopic germinal centers and ultimately leading to IgG4-ROD. This discovery challenges the long-held view that IgG4-ROD is a non-infectious autoimmune disease and provides new directions and perspectives for further research.