Analysis of pathogenicity and development of novel therapy byinflammation-regulating proteins in systemic autoimmune diseases

• Project/Area Number: 22390201
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kyoto University
• Principal Investigator: MIMORI Tsuneyo 京都大学, 大学院・医学研究科, 教授 (10157589)
• Co-Investigator(Renkei-kenkyūsha): FUJII Takao 京都大学, 大学院・医学研究科, 准教授 (70255462) ; USUI Takashi 京都大学, 大学院・医学研究科, 非常勤講師 (90362483) ; OHMURA Koichiro 京都大学, 大学院・医学研究科, 講師 (40432372) ; NOJIMA Takaki 京都大学, 大学院・医学研究科, 非常勤講師 (30327514) ; TANAKA Masao 金沢医科大学, 医学部, 准教授 (10332719)
• Research Collaborator: IGUCHI Mikiko 京都大学, 大学院・医学研究科, 研究生 ; MURAKLAMI Kosaku 大阪赤十字病院, 医師
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: カルパイン / カルパスタチン / FRP / Th17 細胞 / 自己抗体 / 関節リウマチ / 自己免疫疾患 / フォリスタチン関連蛋白 / 炎症性ｻｲﾄｶｲﾝ / T細胞分化 / サイトカイン / 破骨細胞

Research Abstract

We reported previously that autoantibodies to calpastatin (inhibitor of calpain (calcium-dependent neutral proteinase)) and follistatin-related protein (FRP) are found in patients with rheumatoid arthritis. Since these target antigens appeared to show regulatory effects against inflammation, we have intended to clarify the possibility that arthritis may be treated by regulating these autoantigens and autoantibodies. Calpastatin inhibited not only the secretion of IL -6 from fibroblasts, but also affected T cell differentiation, in particular strongly suppress ed the differentiation and activation of Th17 cell. Although FRP has been debated to show different action on regulating of inflammation between human and mouse, we demonstrated that FRP activates inflammation in natural immunity system via TLR4 -CD14 signaling. Analyses of these inflammation-regulating proteins may clarify the pathogenic mechanisms and novel therapeutic strategies of inflammatory arthritis and autoimmune diseases

Research Products

• [Journal Article] Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. (2013)
  • Author(s): Katayama M, Ohmura K, Yukawa N, Terao C, Hashimoto M, Yoshifuji H, Kawabata D, Fujii T, Iwakura Y, Mimori T
  • Journal Title: PLos One Volume: 8(5) Issue: 5 Pages: e62231-e62231
  • DOI: 10.1371/journal.pone.0062231
  • Peer Reviewed
• [Journal Article] NEFA/nucleobindin-2 is a target autoantigen of the anti-Wa antibody and is associated with transfer RNA. (2012)
  • Author(s): Imura Y , Shirai Y , Nojima T, Nakashima R, Yamagata H, Miyachi K, Yoshifuji H, Kawabata D, Ohmura K, Usui T, Fujii T, Mimori T
  • Journal Title: Mod Rheumatol Volume: 22(5) Issue: 5 Pages: 685-94
  • DOI: 10.1007/s10165-011-0582-9
  • NAID: 120005054563
  • Peer Reviewed
• [Journal Article] Type I interferon induces CX3CL1 (fractalkine) and CCL5 (RANTES) production in human pulmonary vascular endothelial cells. (2012)
  • Author(s): Nakano M, Fujii T, Hashimoto M, Yukawa N, Yoshifuji H, Ohmura K, Nakaizumi A, Mimori T
  • Journal Title: Clin Exp Immunol Volume: 170(1) Issue: 1 Pages: 94-100
  • DOI: 10.1111/j.1365-2249.2012.04638.x
  • Peer Reviewed
• [Journal Article] Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance. (2012)
  • Author(s): Kiyama K, Kawabata D, Hosono Y, Kitagori K, Yukawa N, Yoshifuji H, Ohmura K, Fujii T, Mimori T
  • Journal Title: Arthritis Res Ther Volume: 14(2) Issue: 2
  • DOI: 10.1186/ar3810
  • NAID: 120004754361
  • Peer Reviewed
• [Journal Article] Follistatin-related protein/ follistatinlike 1 evokes an innate immune response via CD14 and toll- like receptor 4. (2012)
  • Author(s): Murakami K, Tanaka M, Usui T, Kawabata D, Shiomi A, Iguchi-Hashimoto M, Shimizu M, Yukawa N, Yoshifuji H, Ohmura K, Fujii T, Mimori T
  • Journal Title: FEBS Lett. Volume: 586(4) Issue: 4 Pages: 319-24
  • DOI: 10.1016/j.febslet.2012.01.010
  • Peer Reviewed
• [Journal Article] Quantitative effect of HLA-DRB1 alleles to ACPA levels in Japanese rheumatoid arthritis : no strong genetic impact of shared epitope to ACPA levels after stratification of HLA-DRB1^*09:01 (2012)
  • Author(s): Terao C, Ikari K, et al
  • Journal Title: Annals of the rheumatic diseases Volume: (e-pub) Issue: 6 Pages: 1095-1097
  • DOI: 10.1136/annrheumdis-2011-200907
  • Peer Reviewed
• [Journal Article] ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese. (2012)
  • Author(s): Terao C, Mimori T, et al （21人中21人目）
  • Journal Title: PLoS One Volume: 7 Issue: 7 Pages: e40067-e40067
  • DOI: 10.1371/journal.pone.0040067
  • NAID: 120004754351
  • Peer Reviewed
• [Journal Article] Overexpression of minimal domain of calpastatin suppresses IL-6 production and Th17 development via reduced NF-kB and increased STAT5 signals. (2011)
  • Author(s): Iguchi-Hashimoto M, Usui T, Yoshifuji H, Shimizu M, Kobayashi S, Ito Y, Murakami K, Shiomi A, Yukawa N, Kawabata D, Nojima T, Ohmura K, Fujii T, Mimori T
  • Journal Title: PLoS ONE Volume: 6(10) Issue: 10 Pages: e27020-e27020
  • DOI: 10.1371/journal.pone.0027020
  • Peer Reviewed
• [Journal Article] Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease. (2010)
  • Author(s): Sato T, Fujii T, Yokoyama T , Fujita Y , Imura Y , Yukawa N, Kawabata D, Nojima N, Ohmura K, Usui T, Mimori T
  • Journal Title: Arthritis Rheum. Volume: 62(12) Issue: 12 Pages: 3730-40
  • DOI: 10.1002/art.27700
  • NAID: 120005593598
  • Peer Reviewed
• [Journal Article] DIP2 disco-interacting protein 2 homolog A (Drosophilla) is a candidate receptor for follistatin-related protein/follistatin-like 1. Analysis of their binding with TGF-βsuperfamily proteins. (2010)
  • Author(s): Tanaka M, Murakami K, Ozaki S, Imura Y, Tong XP, Watanabe T, Sawaki T, Kawanami T, Kawabata D, Fujii T, Usui T, Masaki Y, Fukushima T, Jin ZX, Umehara H, Mimori T
  • Journal Title: FEBS J. Volume: 277(20) Issue: 20 Pages: 4278-89
  • DOI: 10.1111/j.1742-4658.2010.07816.x
  • Peer Reviewed
• [Journal Article] Complement drives Th17 cell differentiation and triggers autoimmune arthritis. (2010)
  • Author(s): Hashimoto M, Hirota K, Yoshitomi H, Maeda S, Teradaira S, Akizuki S, Prieto-Martin P, Nomura T, Sakaguchi N, Kohl J, Heyman B, Takahashi M, Fujita T, Mimori T, Sakaguchi S
  • Journal Title: J Exp Med Volume: 207(6) Issue: 6 Pages: 1135-43
  • DOI: 10.1084/jem.20092301
  • Peer Reviewed
• [Journal Article] Aberrant splicing of milk fat globule EGF factor 8 gene in human systemic lupus erythematosus. (2010)
  • Author(s): Yamaguchi H, Fujimoto T, Nakamura S, Ohmura K, Mimori T, Matsuda F, Nagata S.
  • Journal Title: Eur J Immunol Volume: 40(6) Issue: 6 Pages: 1778-85
  • DOI: 10.1002/eji.200940096
  • Peer Reviewed
• [Journal Article] Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease. (2010)
  • Author(s): Sato T, Mimori T, et al(11人中11人目)
  • Journal Title: Arthritis Rheum Volume: 62(12) Pages: 3730-3740
  • NAID: 120005593598
  • Peer Reviewed
• [Journal Article] DIP2 disco-interacting protein 2 homolog A (Drosophilla) is a candidate receptor for follistatin-related protein/follistatin-like 1. Analysis of their binding with TGF-β superfamily proteins. (2010)
  • Author(s): Tanaka M, Mimori T, et al(16人中16人目)
  • Journal Title: FEBS J Volume: 277(20) Pages: 4278-4789
  • Peer Reviewed
• [Journal Article] Complement drives Th17 cell differentiation and triggers autoimmune arthritis. (2010)
  • Author(s): Hashimoto M, Mimori T, et al, (15人中14人目)
  • Journal Title: J Exp Med Volume: 207(6) Pages: 1135-1143
  • Peer Reviewed
• [Presentation] Follistatin-related protein(FRP/FSTL1) exacerbates the inflammatoryprocess of arthritis. (2011)
  • Author(s): Murakami K, Tanaka M, Usui T, Kawabata D, Shiomi A, Iguchi-Hashimoto M, Shimizu M,Yukawa N, Yoshifuji H, Ohmura K, Fujii T, Umehara H, Mimori T
  • Organizer: European League Against Rheumatism (EULAR 2011)
  • Place of Presentation: London
• [Presentation] A new ELISA system for detecting autoantibodies to aminoacyl-tRNA synthetases : Usefulness in myositis and interstitial pneumonia. (2010)
  • Author(s): Nakashima R, Mimori T, et al, (13名中13番目)
  • Organizer: American College of Rheumatorogy 2010
  • Place of Presentation: Atlanta, USA(招待講演)
  • Year and Date: 2010-11-09
• [Book] リウマチ・膠原病内科クリニカルスタンダード (2010)
  • Author(s): 三森経世
  • Total Pages: 331
  • Publisher: 文光堂