2005 Fiscal Year Final Research Report Summary
Analyses on functional relationship of rheumatoid arthritis associated PADI4 gene and the pathogenesis.
| Project/Area Number |
16390285
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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 |
膠原病・アレルギー・感染症内科学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
YAMAMOTO Kazuhiko The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (80191394)
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| Co-Investigator(Kenkyū-buntansha) |
SAWADA Tetsuji The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (50235470)
KOMAGATA Yoshinori The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (60281995)
KAWAHATA Kimito The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (70334406)
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| Project Period (FY) |
2004 – 2005
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| Keywords | rheumatoid arthritis / citrulline / anti-citrullinated peptide antibody / PAD4 |
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| Research Abstract |
We identified RA-associated polymorphisms in PAD4 gene. PAD4 catalyzes the conversion of arginine residues to citrulline in proteins. Recent reports on the high specificity of autoantibodies against citrullinated proteins to RA and the results of our study suggest that citrullination by PAD4 is a fundamental phenomenon of RA
We therefore investigated the citrullinated autoantigens recognized by serum samples from patients with RA. The human chondrocyte cDNA expression library was citrullinated by PAD4 and was immunoscreened with anti-modified citrulline antibodies and sera from patients with rheumatoid arthritis. One immunoreactive cDNA clone included a part of the eukaryotic translation initiation factor 4-G1. Immunoreactivity against a recombinant citrullinated eIF4G1 fragment was observed with high specificity in 50.0% of RA patients. Citrullination of eIF4G1 may thus be involved in the pathogenesis of RA. In the similar method, we obtained human collagen type I as one of the autoantigens using a RA synoviocyte cDNA library. The levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity.
We also found that PAD4 could inactivate antithrombin through citrullination. The abnormal expression or activation of PAD4 in RA synovium is suggested to be responsible for the high level of citrullinated antithrombin in RA plasma. Local inhibition of antithrombin activity in RA synovium might lead to the excessive angiogenesis, fibrin deposition and inflammation of the tissue.
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[Journal Article] A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities.2005
Author(s)
Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, Bae SC, Tokuhiro S, Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo S, Yumura W, Mimori A, Koike T, Nakamura Y, Sasazuki T, Yamamoto K.
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Journal Title
Nature Genet. 37
Pages: 478-485
Description
「研究成果報告書概要(欧文)」より
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