Function of Immune Checkpoints in IgG4-Related Disease with Lacrimal Gland Involvement: Clinical Features, Serum IgG4 Level, Immunohistochemical Landscape, and Treatment Responses

Abstract

IgG4-related disease (IgG4-RD) is an autoimmune condition marked by IgG4-positive plasma cell infiltration, causing inflammation, fibrosis, and tumor-like lesions, especially in the lacrimal gland (LG). Current diagnostic criteria, based primarily on serum IgG4 levels, face limitations in predicting clinical outcomes and treatment responses. To address this, we conducted a multiplex immaunohistochemical analysis of LG tissues to assess immune checkpoint interactions and immune cell distribution in relation to mass size, fibrosis, and treatment response. Our findings revealed that PD-L1 (Programmed Death-Ligand 1), an immune checkpoint molecule, plays a key role in shaping an immunosuppressive environment that varies by clinical group. In non-responsive patients, increased co-expression of PD-L1 and CD11c+ dendritic cells (DCs) suggested a link to treatment resistance. Spatial analysis highlighted more active immune responses in non-fibrotic areas, while fibrotic regions exhibited stabilized immune interactions driven by PD-L1 expression. These results indicate that PD-L1 contributes to immune regulation and disease progression in IgG4-RD and emphasize its potential as a therapeutic target. This study provides new insights into the immunological landscape of IgG4-RD and paves the way for the development of personalized treatment strategies.