2000 Fiscal Year Final Research Report Summary
Study on pathophysiological mechanism of autoantibody production in pemphigus
| Project/Area Number |
11470185
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Keio University |
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Principal Investigator |
AMAGAI Masayuki Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)
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| Co-Investigator(Kenkyū-buntansha) |
HARUMI Suzuki Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (70235985)
KOYASU Shigeo Keio University School of Medicine, Professor, 医学部, 教授 (90153684)
NISHIKAWA Takeji Keio University School of Medicine, Professor, 医学部, 教授 (50051579)
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| Project Period (FY) |
1999 – 2000
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| Keywords | autoimmune diseases / pemphigus / animal model / desmoglein / autoantibody / tolerance / B cell / knockout mouse |
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| Research 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, we had dual approaches using human materials of PV patients and a mouse model for PV.To examine cellular mechanisms underlying the autoantibody production in PV patients, we have successfully developed an Enzyme-Linked Immunospot (ELISPOT) assay which was able to detect Dsg3-specific autoimmune B cells quantitatively. The in vitro anti-Dsg3 Ab production was abolished when CD4^+ cells were depleted or when anti-HLA-DR or anti-HLA-DQ monoclonal Ab was added to the cultures, suggesting the important role of HLA class II-restricted CD4^+ T cells in the autoAb production in PV.Using a novel PV mouse model involving Dsg3 knockout mice, we investigated the mechanisms of tolerance loss 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.
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[Publications] Wu H,Wang ZH,Yan A,Lyle S,Fakbarzadeh S,Wahl JK,Wheelock MJ,Ishikawa H,Uitto J,Amagai M,Stanley JR: "Protection against pemphigus foliaceus by desmoglein 3 in neonates."N Eng J Med. 343. 31-35 (2000)
Description
「研究成果報告書概要(和文)」より
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[Publications] Wu H, Wang ZH, Yan A, Lyle S, Fakharzadeh S, Wahl JK, Wheelock MJ, Ishikawa H, Uitto J, Amagai M, Stanley JR: "Protection against pemphigus foliaceus by desmoglein 3 in neonates."N Eng J Med. 343. 31-35 (2000)
Description
「研究成果報告書概要(欧文)」より
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