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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\u2212\/\u2212 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\u2212\/\u2212 and Fcgr2b+\/\u2212 mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and Fc\u03b3RIIB-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 Fc\u03b3RIIB 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>","DOI":"10.4049\/jimmunol.2100781","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T12:05:22Z","timestamp":1641557122000},"page":"582-593","source":"Crossref","is-referenced-by-count":8,"title":["IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3\u2013Specific B Cell Receptor Knock-in Mouse"],"prefix":"10.1093","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7678-0398","authenticated-orcid":false,"given":"Hisashi","family":"Nomura","sequence":"first","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-8821","authenticated-orcid":false,"given":"Hayato","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0334-5760","authenticated-orcid":false,"given":"Yuko","family":"Kase","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yamagami","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Egami","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-8950","authenticated-orcid":false,"given":"Hisato","family":"Iriki","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1173-0538","authenticated-orcid":false,"given":"Miho","family":"Mukai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0211-1738","authenticated-orcid":false,"given":"Aki","family":"Kamata","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-4165","authenticated-orcid":false,"given":"Hideki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Department of Oral Microbiology, Tokushima University Graduate School of Biomedical Sciences , Tokushima,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Ishikura","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-0375","authenticated-orcid":false,"given":"Takashi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taketo","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical University , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9585-3038","authenticated-orcid":false,"given":"Shigeo","family":"Koyasu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-7052","authenticated-orcid":false,"given":"Masayuki","family":"Amagai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,1]]},"reference":[{"key":"2025021008525755800_r1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/337562a0","article-title":"Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody 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Dermatol."},{"key":"2025021008525755800_r15","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1172\/JCI8748","article-title":"Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus","volume":"105","author":"Amagai","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2025021008525755800_r16","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.4049\/jimmunol.170.4.2170","article-title":"Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3","volume":"170","author":"Tsunoda","year":"2003","journal-title":"J. Immunol."},{"key":"2025021008525755800_r17","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.ajpath.2011.04.015","article-title":"Pathogenic relevance of IgG and IgM antibodies against desmoglein 3 in blister formation in pemphigus vulgaris","volume":"179","author":"Tsunoda","year":"2011","journal-title":"Am. J. Pathol."},{"key":"2025021008525755800_r18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1084\/jem.188.1.169","article-title":"B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice","volume":"188","author":"Litzenburger","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025021008525755800_r19","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Kr\u00e4mer","year":"2014","journal-title":"Bioinformatics"},{"key":"2025021008525755800_r20","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1002\/1521-4141(200002)30:2<689::AID-IMMU689>3.0.CO;2-I","article-title":"B cell clonal elimination induced by membrane-bound self-antigen may require repeated antigen encounter or cell competition","volume":"30","author":"Lang","year":"2000","journal-title":"Eur. J. 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