Study on the Key Mechanisms of Abnormal T Cell Activation and Differentiation in IgG4-Related Ophthalmic Disease

Immunoglobulin-G4 related disease (IgG4-RD) is a newly defined immune-mediated chronic inflammatory disease with fibrosis, characterized by lymphoplasmacytic infiltration predominantly consisting of IgG4+ plasma cells, along with storiform fibrosis, obliterative phlebitis, and eosinophil infiltration. The most common clinical manifestations of IgG4-RD include significantly elevated serum IgG4 levels and mass-like lesions, which can affect nearly any part of the body, leading to compression and irreversible damage to affected organs and surrounding tissues, potentially resulting in organ failure. Despite reports estimating the prevalence of IgG4-RD to be between (0.28~1.08)/100,000, the actual prevalence might be higher due to its recent definition, limited awareness among clinicians and patients, and its insidious onset.

Immunoglobulin-G4 related ophthalmic disease (IgG4-ROD) refers to IgG4-RD mass-like lesions involving the lacrimal gland, extraocular muscles, supraorbital nerve, infraorbital nerve, and other orbital structures, leading to orbital lesions. Among these, lacrimal gland involvement is the most common, manifesting as painless, unilateral or bilateral swelling, sometimes accompanied by foreign body sensation or eye discomfort. Extraocular muscle involvement can present as muscle enlargement, potentially causing proptosis, blurred vision, and diplopia in severe cases. Orbital mass lesions may also compress the optic nerve, leading to irreversible vision loss. While there is currently no cure for IgG4-ROD, glucocorticoids are used as the first-line treatment to control inflammation and fibrosis associated with the mass-like lesions. IgG4-ROD is prone to relapse, and though there are no studies specifically on its recurrence rate, different studies have reported relapse rates of IgG4-RD patients during follow-up ranging from 24% to 63%. The exact etiology and pathogenesis of IgG4-ROD remain unclear, and further elucidation of these aspects would facilitate the identification of new therapeutic targets, reduce relapse rates, and potentially achieve a cure.

Multiple studies on various forms of IgG4-RD suggest a critical role of T cells in the pathogenesis of IgG4-RD, including IgG4-ROD. First, CD4+ T cells constitute the majority of infiltrating lymphocytes in the lesions of IgG4-RD. These CD4+ T cells induce B cell proliferation and class-switching through cytokine secretion and contribute to tissue fibrosis. Additionally, IgG4-RD patients treated with rituximab exhibit high relapse rates, with post-relapse B cell clones expanding differently compared to pre-treatment . This evidence strongly supports the central role of T cells in IgG4-RD. Among the T cell subpopulations implicated in IgG4-RD pathogenesis, T follicular helper cells (Tfh) and CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are particularly notable. Tfh cells promote ectopic germinal center formation and B cell class-switching to IgG4+ plasma cells through IL-21 secretion, while CD4+ CTLs contribute to tissue fibrosis by secreting TGF-β, IL-1β, and IFN-γ . However, the mechanisms underlying abnormal T cell activation and differentiation in both IgG4-ROD and other IgG4-RD remain poorly understood.

This study aims to investigate key pathways involved in abnormal T cell activation and differentiation in IgG4-ROD by conducting a series of in vitro experiments using surgical tissue samples, peripheral blood, and tear fluid from patients with IgG4-ROD. These experiments include RNA sequencing (RNA-Seq), enzyme-linked immunosorbent assays (ELISA), and in vitro cell co-culture. The goal is to identify critical pathways in the pathogenesis of IgG4-ROD and to clarify their roles in the disease process, providing new therapeutic targets to reduce the recurrence rate of IgG4-ROD. This research may also offer insights into the mechanisms and treatment of other IgG4-related diseases.

Study Population