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

• Published in: The Journal of immunology (1950) Vol. 208; no. 3; pp. 582 - 593
• Main Authors: Nomura, Hisashi, Wada, Naoko, Takahashi, Hayato, Kase, Yuko, Yamagami, Jun, Egami, Shohei, Iriki, Hisato, Mukai, Miho, Kamata, Aki, Ito, Hiromi, Fujii, Hideki, Ishikura, Tomoyuki, Koseki, Haruhiko, Watanabe, Takashi, Yamada, Taketo, Ohara, Osamu, Koyasu, Shigeo, Amagai, Masayuki
• Format: Journal Article
• Language: English
• Published: United States 01.02.2022
• Subjects: Adult; Aged; Animals; Autoimmunity - immunology; B-Lymphocytes - immunology; Desmoglein 3 - genetics; Desmoglein 3 - immunology; Female; Gene Knock-In Techniques; Humans; Immunoglobulin Class Switching - immunology; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin M - genetics; Immunoglobulin M - immunology; Keratinocytes - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Pemphigus - genetics; Pemphigus - immunology; Pemphigus - pathology; Receptors, IgG - genetics; Receptors, IgG - metabolism
• DOI: 10.4049/jimmunol.2100781
• ISSN: 0022-1767

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 Ca 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 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, deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in and mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of 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.