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

Abstract

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.

Keywords: ALLERGY; AUTOIMMUNE DISEASE; IMMUNOLOGY; PANCREATIC ANTIBODIES; PANCREATITIS.

Figure 1. Unique structural and functional features of IgG4. IgG4 is characterised by unique structural features leading to its anti-inflammatory properties. Residues S228 in the hinge region and R409 in the CH3 domain enable antigen-binding fragment (Fab) arm exchange, resulting in bispecific antibodies and practical monovalency. This monovalency reduces antigen cross-linking and immune complex formation. The residues F234, G327 and S331 in the crystallisable fragment (Fc) region weaken interactions with activating Fcγ receptors and impair complement activation. These features lead to reduced antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

Figure 2. Pathophysiological roles of IgG4. IgG4 exhibits both protective and pathogenic activities in various immunological contexts. Left: IgG4’s protective roles include reducing mast cell degranulation and antigen presentation in allergies and parasitic infections by competing with IgE for antigen binding. It also supports therapeutic tolerance by reducing antigen presentation. Right: Pathogenic activities include IgG4’s role in cancer, where it suppresses immune responses by competing with other IgG subclasses for antigen binding and reducing crystallisable fragment (Fc) receptor-mediated immune responses. Additionally, IgG4 can inhibit therapeutic antibody efficacy by interfering with Fc effector mechanisms. In mRNA vaccination, prolonged antigen exposure drives IgG4 class switching, potentially reducing Fc effector functions and vaccine-induced protection.