IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3–Specific B Cell Receptor Knock-in Mouse

  • Hisashi Nomura
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Naoko Wada
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Hayato Takahashi
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Yuko Kase
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Jun Yamagami
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Shohei Egami
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Hisato Iriki
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Miho Mukai
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Aki Kamata
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Hiromi Ito
    Department of Dermatology, Keio University School of Medicine , Tokyo,
  • Hideki Fujii
    Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo,
  • Tomoyuki Ishikura
    Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences , Kanagawa,
  • Haruhiko Koseki
    Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences , Kanagawa,
  • Takashi Watanabe
    Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences , Kanagawa,
  • Taketo Yamada
    Department of Pathology, Saitama Medical University , Saitama,
  • Osamu Ohara
    Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences , Kanagawa,
  • Shigeo Koyasu
    Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo,
  • Masayuki Amagai
    Department of Dermatology, Keio University School of Medicine , Tokyo,

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<jats:title>Abstract</jats:title> <jats:p>Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2−/− mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b−/− and Fcgr2b+/− mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.</jats:p>

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