title: Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris.
abstract: Mechanisms of tolerance break against desmoglein 3 (Dsg3) in patients with pemphigus vulgaris (PV) producing pathogenic anti-Dsg3 IgG autoantibodies are unclear. In this study, using a novel PV mouse model involving Dsg3 knockout mice, we investigated the mechanisms leading to production of autoantibodies against Dsg3. Adoptive transfer of Dsg3(-/-) splenocytes immunized with recombinant mouse Dsg3 to Rag2(-/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3(-/-), Dsg3(+/-) or Dsg3(+/+) mice were mixed with various combinations and transferred to Rag2(-/-) mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3(-/-) T and Dsg3(-/-) B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV.
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsunoda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Manabu
authors.initials: M
authors.lastname: Ohyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagai
authors.forename: Takeji
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D015820:Cadherins / Q000276:immunology*; D002460:Cell Line; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D051184:Desmoglein 3; D004195:Disease Models, Animal; D004817:Epidermis / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000473:pathology; D009687:Nuclear Proteins; D010392:Pemphigus / Q000276:immunology*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000276:immunology; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015820:Cadherins; D004268:DNA-Binding Proteins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D007074:Immunoglobulin G; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2