B cells have been classically involved in immune responses through antigen 26 presentation to T cells, secretion of cytokines and differentiation to plasma cells for 27 immunoglobulin production. Human B cells express four subclasses of IgG (IgG1, 28 IgG2, IgG3, IgG4), and each subclass has different biological functions. The structure 29 and biological functions of IgG4 are less well understood, in part due to the lack of a 30 functional correlate in mice. IgG4 is the least abundant subclass of IgG in serum 31 accounting for approximately 4% of total IgG, while its levels can reach up to 75% of 32 total IgG after chronic exposure to antigen, such as allergen immunotherapy (AIT). 1, 2 33 Because of its unique structural features in the hinge region, IgG4 has several non-34 inflammatory properties, which are listed below (Table 1). IgG4 has low affinity for 35 the classical activating Fc receptors. It can form bispecific, 36 functionally monovalent antibodies through half molecule exchange, also called Fab 37 arm exchange. 3 Two heavy chains of IgG4 separate to form „half-molecules‟ 38 comprising just one heavy and one light chain. Following this, half-molecules of any 39 different specificity can recombine, and create bi-specific antibodies. Bispecific 40 antibodies lack the ability to cross-link allergens and do not form immune complexes. 41 An additional mechanism by which specific IgG can downregulate the activation of 42 mast cells and basophils is by cross-linking of Fc RI and Fc RIIb with allergen-43 complexed specific IgE and IgG. 4 A third non-inflammatory role of IgG4 results 44 from the disrupted C1q binding site leading to the inability to activate complement. 5 45 A fourth role of specific IgG4 to hinder mast cell and basophil degranulation is 46 competition with specific IgE for allergen binding as a „blocking antibody‟. 2 47 Increased serum allergen-specific IgG4 levels are associated with AIT and healthy 48 individuals who have been exposed to relatively high doses of allergens, such as non-49 allergic beekeepers and cat owners. 1 In contrast, recent evidence has also revealed a 50 deleterious role for IgG4 in anti-tumor responses in malignant melanoma by hindering 51 IgG1-mediated anti-tumor immunity. 5 Furthermore, a variety of inflammatory 52 diseases have now been classified under the term „IgG4-related disease‟ in which 53 IgG4 serum levels are often raised, and IgG4-positive plasma cell infiltrates are found. 54 5 However, the contribution of IgG4 to the pathogenesis of these diseases still remains 55 unclear. 56