Potential roles of antibodies with different classes in IgG4‐related diseases

Abstract Immunoglobulin G4‐related disease (IgG4‐RD), first identified two decades ago, is an immune‐mediated pro‐inflammatory and profibrotic disease entity affecting multiple organs. The main histopathological features are a dense lymphoplasmacytic infiltrate rich in IgG4 + plasma cells, storiform fibrosis, and obliterative phlebitis. The precise immunopathology of IgG4‐RD is still unclear. Substantial research has validated the central role of B cells in IgG4‐RD, which can be further demonstrated by the responsiveness to B cell depletion treatment and the identification of multiple autoantibodies. Whether and how antibodies are pathogenic remains mechanistically undefined, warranting systematic investigation. Through integrative analysis of experimental studies and clinical findings, this review discussed the common characteristics of different classes of antibodies and their potential corresponding unique mechanisms involved in IgG4‐RD. Despite belonging to distinct classes, antibodies share conserved structural features that mediate common effector functions including neutralization and opsonization. In IgG4‐RD pathogenesis, the soluble IgG4 form appears non‐pathogenic, whereas its membrane‐bound counterpart demonstrates enhanced antigen‐binding avidity and facilitates epitope spreading cascades. Among other IgG subclasses, IgG1 emerges as a more potentially pathogenic subclass of antibody. Emerging evidence from multidisciplinary investigations progressively delineates the pathogenetic contributions of IgE and IgM. Systematic interrogation of antibodies with different classes and their pathogenic mechanisms in IgG4‐RD advances our understanding of disease immunopathogenesis while unveiling novel therapeutic targets with translational implications.