The dual role of IgG4 in immunity: bridging pathophysiology and therapeutic applications

IgG4 antibodies exhibit unique structural and functional properties, which distinguish them from other IgG subclasses. Among clinicians, IgG4 has been primarily associated with IgG4-related diseases (IgG4-RDs), such as autoimmune pancreatitis, where its role has been a focus of intense discussion. However, growing evidence reveals that IgG4 is involved in a broader spectrum of immune-regulatory processes, extending beyond IgG4-RDs and positioning it as a key modulator of immune tolerance. In this context, several specific features allow IgG4 to play dual roles, serving as a protective factor in immune regulatory settings, such as allergic responses and antibody therapies that require tolerance induction towards target cells, while its role in IgG4-RDs remains uncertain, potentially contributing to disease or mitigating tissue damage. This review examines the pathophysiological roles of IgG4 in the regulation of immune responses, highlighting its involvement in both homoeostasis and disease. Furthermore, it explores the therapeutic potential of harnessing IgG4’s unique features, not only for IgG4-associated diseases, but also for other indications, where promoting beneficial IgG4 responses could offer therapeutic advantages.