Epstein-Barr Virus-Induced Upregulation of GPR183: A Potential Upstream Mechanism in IgG4-Related Ophthalmic Disease

Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is the most common subtype of IgG4-related disease (IgG4-RD), yet its pathogenic mechanisms remain poorly understood. Ectopic germinal centers are a hallmark histopathological feature of IgG4-ROD, but the molecular drivers underlying their formation remain unclear. This study aimed to identify potential upstream triggers of IgG4-ROD and novel therapeutic targets.

Fourteen patients with IgG4-ROD and 13 controls (9 with lacrimal gland prolapse and 4 with chronic dacryoadenitis) were enrolled. Lacrimal gland specimens were analyzed using bulk RNA sequencing (RNA-seq), multiplex immunofluorescence, flow cytometry, and quantitative real-time PCR (qPCR). Public bulk and single-cell RNA-seq datasets were further analyzed.

GPR183 was the only gene consistently upregulated across lacrimal gland, salivary gland, peripheral blood, and retroperitoneal fibrosis tissues from patients with IgG4-RD. GPR183 was broadly expressed across multiple immune cell populations in lacrimal glands. Multiplex immunofluorescence demonstrated prominent GPR183 expression within ectopic germinal centers, particularly in B-lymphocyte-rich regions. The qPCR revealed a significantly higher Epstein-Barr virus (EBV) positivity rate in IgG4-ROD lacrimal glands than in controls (85.7% vs. 15.4%, P < 0.001). EBV DNA copy number positively correlated with serum IgG4 levels (adjusted R² = 0.79, P < 0.01). EBV markers EBNA1 and LMP1 were co-expressed with GPR183. Single-cell RNA-seq showed that early EBV infection induced GPR183 expression in T and B lymphocytes and was associated with B-lymphocyte differentiation.

Our findings suggest that EBV-induced GPR183 upregulation potentially promotes ectopic germinal center formation and contributes to the pathogenesis of IgG4-ROD.