IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3–Specific B Cell Receptor Knock-in Mouse
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- Hisashi Nomura
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Naoko Wada
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Hayato Takahashi
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Yuko Kase
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Jun Yamagami
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Shohei Egami
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Hisato Iriki
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Miho Mukai
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Aki Kamata
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Hiromi Ito
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
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- Hideki Fujii
- †Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan;
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- Tomoyuki Ishikura
- ¶Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan;
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- Haruhiko Koseki
- ¶Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan;
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- Takashi Watanabe
- ‖Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan;
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- Taketo Yamada
- #Department of Pathology, Saitama Medical University, Saitama, Japan; and
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- Osamu Ohara
- ‖Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan;
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- Shigeo Koyasu
- †Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan;
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- Masayuki Amagai
- *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
説明
<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>
収録刊行物
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- The Journal of Immunology
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The Journal of Immunology 208 (3), 582-593, 2022-02-01
Oxford University Press (OUP)
