RT Journal Article
SR Electronic
T1 Inhibition of immunoglobulin class-switching prevents pemphigus onset in desmoglein 3-specific B cell receptor knock-in mouse
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.23.445300
DO 10.1101/2021.05.23.445300
A1 Hisashi Nomura
A1 Naoko Wada
A1 Hayato Takahashi
A1 Yuko Kase
A1 Jun Yamagami
A1 Shohei Egami
A1 Hisato Iriki
A1 Miho Mukai
A1 Aki Kamata
A1 Hiromi Ito
A1 Hideki Fujii
A1 Tomoyuki Ishikura
A1 Haruhiko Koseki
A1 Takashi Watanabe
A1 Taketo Yamada
A1 Osamu Ohara
A1 Shigeo Koyasu
A1 Masayuki Amagai
YR 2021
UL http://biorxiv.org/content/early/2021/05/23/2021.05.23.445300.abstract
AB 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 FcγRIIB-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 FcγRIIB signaling is one of the key predispositions to break this tolerogenic state.Competing Interest StatementThe authors have declared no competing interest.