Immunoglobulin G4 (IgG4)

Immunoglobulin G4 (IgG4) is the least abundant subclass of IgG in human serum but plays a pivotal role in immune regulation and the induction of peripheral tolerance. It is characterized by unique structural properties, including the ability to undergo Fab-arm exchange, which renders the molecule functionally monovalent and prevents the formation of large, pro-inflammatory immune complexes (van der Neut Kolfschoten et al., 2007, Science). In the context of allergen immunotherapy (AIT), the induction of allergen-specific IgG4 is a hallmark of successful treatment and clinical desensitization. These antibodies function as blocking antibodies by competing with IgE for allergen binding, thereby inhibiting the activation of mast cells and basophils (Shamji et al., 2011, JACI). Furthermore, IgG4 can engage the inhibitory receptor FcγRIIb, providing an additional layer of negative regulation on immune cell signaling (Aalberse et al., 2009, Immunology). While beneficial in allergy, excessive or dysregulated IgG4 production is associated with IgG4-related disease, a systemic condition characterized by fibro-inflammatory lesions (Stone et al., 2012, NEJM). As a biomarker, IgG4 levels are frequently monitored to assess the efficacy of subcutaneous and sublingual immunotherapy (Davies et al., 2011, JACI).

Other names

IgG4 subclassAllergen-specific IgG4Blocking antibodyAntigen-specific IgG4

In the context of immunotherapy, IgG4 acts as a blocking antibody that competes with IgE for allergen binding, preventing the cross-linking of FcεRI on mast cells and basophils. It also facilitates inhibitory signaling by co-aggregating the inhibitory receptor FcγRIIb with activating receptors (Akdis & Akdis, 2014, JACI).