2004 Fiscal Year Final Research Report Summary
Clarification of pathophysiological mechanisms of autoimmune skin disease, pemphigus
| Project/Area Number |
13854017
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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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) |
NISHIKAWA Takeji Keio University, School of Medicine, Professor, 医学部, 教授 (50051579)
TANAKA Masaru Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (40188339)
ISHIKO Akira Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (10202988)
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
IWASAKI Toshiro Tokyo University of Agriculture and Technology, Department of Veterinary Internal Medicine, Professor, 獣医学部, 教授 (50262754)
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| Project Period (FY) |
2001 – 2004
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| Keywords | autoimmune / skin infection / pemphigus / cadherin / desmoglein / Staphylococcus aureus / autoantibody / model mouse |
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| Research Abstract |
Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies directed against desmogleins (Dsg), cadherin-type cell-cell adhesion molecules found in desmosomes. The goal of this study is to clarify the immunological mechanisms of autoimmune diseases by taking two unique approaches ; analyzing pemphigus model mice and investigating the contact points of skin infection and autoimmunity.
We have achieved the following progresses ; 1)isolated 8 clones for pathogenic and non-pathogenic AK-series anti-Dsg3 mAbs from PV model mice and showed the epitope is a critical factor determining the pathogenicity, 2)developed B cell transgenic mice from cDNA for the variable regions of AK7 mAb and analyzed the fate of the autoreactive B cells, 3)developed several Dsg3-reactive T cell clones from Dsg3-/- mice and analyzed their roles in the production of pathogenic anti-Dsg3 Abs, 4)clarified the molecular mechanisms that exfoliative toxins (ETA,ETB, and ETD) produced by S.aureus, which causes SSSS and bullous impetigo, are Dsg1-specific serine proteases, 5)demonstrated that some patients with SSSS developed low titers of anti-Dsg1 IgG autoantibodies.
We further achieved the following unexpected progresses ; 6)found a potentially new peripheral B cell tolerance mechanism by showing the elimination of Dsg3-specific B cells from peripheral lymphoid organs by injection of pathogenic AK23 mAb, 7)demonstrated the autoimmune reaction against a novel desmoglein isoform, Dsg4, in subsets of pemphigus patients, providing a new framework for better understanding the onset of autoimmune diseases including autoimmune alopecia.
We have established a unique physiological system for organ-specific autoimmune diseases by using PV model mice, Dsg3-specific B cell transgenic mice, and, in the near future, Dsg3-specific T cell transgenic mice. We aimed to establish a novel standard experimental system to uncover the mysteries of autoimmunity and tolerance to peripheral antigens.
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Research Products
(14 results)
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[Book] Dermatology2003
Author(s)
Amagai M
Total Pages
449-462
Publisher
Harcourt Health Sciences
Description
「研究成果報告書概要(和文)」より
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