The Emerging Role of IgG4 in Rheumatology

Abstract

Immunoglobulin G4 (IgG4) is the least abundant IgG subclass and possesses unique structural and functional properties, including Fab-arm exchange, weak complement activation, and reduced Fc receptor binding. These features confer a predominantly immunomodulatory profile that distinguishes IgG4 from other IgG subclasses. Historically associated with allergic responses and immune tolerance, IgG4 has gained increasing attention following the recognition of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory condition characterized by tumefactive lesions, IgG4-positive plasma cell infiltration, and storiform fibrosis.

Beyond IgG4-RD, IgG4 responses have also been described in several rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, anti-neutrophil cytoplasmic autoantibody-associated vasculitis, and Sjögren disease. In these diseases, IgG4 may function as a marker of chronic immune activation, an immunomodulatory adaptation, or contribute to disease pathogenesis; however, its precise role remains poorly understood. Elevated serum IgG4 levels or tissue infiltration by IgG4+ plasma cells lacks disease specificity and should be interpreted within an appropriate clinical and histopathologic context.

This review summarizes the biological features of IgG4, its established association with IgG4-RD, and its emerging significance across rheumatic diseases. Understanding the context-dependent role of IgG4 may improve diagnostic interpretation and advance our understanding of immune-mediated disease in rheumatology.