Although immunoglobulin class-switching is essential for humoral immunity, its role in B-cell immune tolerance remains unclear. Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3, an adhesion molecule of keratinocytes. In this study, we generated knock-in mice that express anti-Dsg3 AK23 autoantibodies. Knock-in B cells developed normally in vivo and showed Ca2+ influx upon IgM cross-linking in vitro. The mice predominantly produced circulating AK23 IgM but little IgG antibodies. Although no IgG deposition or blister formation was observed in Dsg3-bearing tissues, Dsg3 immunization forced to induce pemphigus phenotype after class-switching to IgG in vivo. Transcriptomic analysis revealed that FCGR2B and FcgRIIB-related genes were downregulated in B cells from peripheral blood of pemphigus patients. Indeed, in AK23 knock-in mice, Fcgr2b deficiency or haploinsufficiency spontaneously led to class-switching, AK23 IgG production, and pemphigus phenotype development. Thus, inhibition of pathogenic class-switching is a crucial tolerogenic process to prevent pemphigus onset, where attenuated FcgRIIB signaling is one of the key predispositions to break this tolerogenic state.
Global gene regulation during activation of immunoglobulin class switching in human B cells