Inhibition of immunoglobulin class-switching prevents pemphigus onset in desmoglein 3-specific B cell receptor knock-in mouse

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.

Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome

Key PointsThe CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA. Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching.