Allergen-specific immunoglobulin G4 (IgG4) (IgG4)

Allergen-specific immunoglobulin G4 (IgG4) and the B cells that produce it are critical components of the immune system's regulatory response to allergens [1, 2]. Unlike IgE, which triggers immediate hypersensitivity reactions, IgG4 acts as a "blocking antibody" that promotes immune tolerance by competing with IgE for allergen binding and signaling through the inhibitory receptor FcγRIIb on mast cells and basophils [6, 7]. This dual mechanism prevents the cross-linking of high-affinity IgE receptors (FcεRI), thereby inhibiting the release of inflammatory mediators like histamine [1, 6]. In clinical practice, the induction of allergen-specific IgG4 is a hallmark of successful allergen immunotherapy (AIT) and serves as a key biomarker for therapeutic efficacy [4, 5, 18]. Beyond its protective role in allergy, dysregulated IgG4 production is associated with IgG4-related disease (IgG4-RD), a fibro-inflammatory condition where IgG4-producing plasmablasts and plasma cells infiltrate various organs [13, 14]. In this context, these cells become therapeutic targets for depletion using monoclonal antibodies such as rituximab (anti-CD20) or inebilizumab (anti-CD19) [16, 17]. Additionally, novel passive immunotherapy approaches are being developed, utilizing lab-engineered allergen-specific IgG4 monoclonal antibodies (e.g., REGN1908/1909 for cat allergy and IGNX001 for peanut allergy) to provide rapid protection against allergic reactions by neutralizing allergens before they can interact with IgE [19, 22, 23, 24].

Other names

Blocking antibodies [1, 3, 18]Antigen-specific IgG4 [1, 31]sIgG4 [4, 5, 18]Tolerogenic antibodies [3, 8]IgG4-producing B cells [13, 17]

Competitive inhibition of IgE binding to allergens and co-engagement of the inhibitory receptor FcγRIIb to suppress effector cell activation [1, 6, 7]. In IgG4-related disease, therapeutic strategies focus on the depletion of CD19+ or CD20+ B cells and plasmablasts to reduce pathogenic IgG4 production and tissue infiltration [14, 16, 17].