Exploration of pathogenetic role of citrullinated ITIH4 in rheumatoid arthritis

• Project/Area Number: 18K08403
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Tsukuba
• Principal Investigator: Matsumoto Isao 筑波大学, 医学医療系, 准教授 (30343081)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 関節リウマチ / ITIH4 / シトルリン化蛋白 / 好中球

Outline of Final Research Achievements

We found specific disease plasma marker, citrullinated inter-alpha-trypsin inhibitor heavy chain 4 (cit-ITIH4) in plasma in pGIA model and rheumatoid arthritis (RA). Cit-ITIH4 is highly concentrated in synovial fluid than plasma in RA. Recombinant cit-ITIH4 enhanced neutrophil migration and complement activation, suggesting exacerbating role in arthritis.

Academic Significance and Societal Importance of the Research Achievements

関節炎発症時は局所でITIH4濃度及びcit-ITIH4が上昇し、その過程で関節局所に流入する好中球がPAD4発現を上昇させ、局所でのシトルリン化を促すことが判明した(Osada et al. Clin.Exp.Immunol.2021)。これらより、まず血漿cit-ITIT4のELISA同定キットの作成を進めている。また、ITIH4自体の関節炎への関与をより明らかにするために、欠損マウスを用いて研究を進める。関節炎症に特化した制御メカニズムが明らかになり、新たな治療ターゲットの創生が望まれる。

Research Products

• [Journal Article] Citrullinated inter-alpha-trypsin inhibitor heavy chain 4 in arthritic joints and its potential effect in the neutrophil migration. (2021)
  • Author(s): Osada A, Matsumoto I, Mikami N, Ohyama A, Kurata I,Kondo Y, Tsuboi H, Ishigami A, Sano Y, Arai T, Ise N, Sumida T.
  • Journal Title: Clin Exp Immunol Volume: 203 Issue: 3 Pages: 385-399
  • DOI: 10.1111/cei.13556
  • Peer Reviewed
• [Journal Article] Splice variant of STEAP4 localizes in the nucleus, making it a possible transcriptional regulator of IL-6 production. (2019)
  • Author(s): Ebe H, *Matsumoto I, Osada A, Kurata I, Kawaguchi H, Kondo Y, Tsuboi H, Sumida T.
  • Journal Title: Mod Rheumatol. Volume: 29 Pages: 714-716
  • Peer Reviewed
• [Journal Article] Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interlukin-6. (2019)
  • Author(s): Kawaguchi H, *Matsumoto I, Osada A, Kurata I, Ebe H, Tanaka Y, Inoue A, Umeda N, Kondo Y, Tsuboi H, Ishigami A, Sumida T.
  • Journal Title: Mod Rheumatol. Volume: 29 Pages: 964-969
  • Peer Reviewed
• [Journal Article] Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis. (2019)
  • Author(s): Kurata I, *Matsumoto I, Ohyama A, Osada A, Ebe H, Kawaguchi H, Kaneko S, Kondo Y, Tsuboi H, Tomioka A, Kaji H, Sumida T
  • Journal Title: Ann Rheum Dis. Volume: 78 Pages: 1488-1496
  • Peer Reviewed
• [Journal Article] Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interlukin-6. (2019)
  • Author(s): Kawaguchi H, *Matsumoto I, Osada A, Kurata I, Ebe H, Tanaka Y, Inoue A, Umeda N, Kondo Y, Tsuboi H, Ishigami A, Sumida T.
  • Journal Title: Modern Rheumatology Volume: in press
  • Peer Reviewed
• [Journal Article] Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis. (2018)
  • Author(s): Kawaguchi H, *Matsumoto I, Osasda A, Kurata I, Ebe H, Tanaka Y, Inoue A, Umeda N, Kondo Y, Tsuboi H, Shinkai Y, Kumagai Y, Ishigami A, Sumida T.
  • Journal Title: Arthritis Res Ther Volume: 20 Pages: 66-66
  • NAID: 120007128092
  • Peer Reviewed
• [Presentation] Inter-alpha-trypsin inhibitor heavy chain 4（ITIH4）のシトルリン化機構と補体系への関与の検討 (2021)
  • Author(s): 長田侑、三上奈津子、大山綾子、藏田泉、近藤裕也、坪井洋人、松本功
  • Organizer: 第65回日本リウマチ学会総会
• [Presentation] 関節リウマチにおけるT細胞と抗シトルリン化蛋白抗体のトピックス (2019)
  • Author(s): 松本 功
  • Organizer: 第28回日本シェーグレン症候群学会(徳島)
  • Invited
• [Presentation] TNFとその阻害メカニズムupdate-関節リウマチを中心に- (2019)
  • Author(s): 松本 功
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] 関節リウマチの寛解導入・維持療法を再考する (2019)
  • Author(s): 松本 功
  • Organizer: 第63回日本リウマチ学会総会・学術集会（京都）
  • Invited
• [Remarks] 筑波大学 膠原病リウマチアレルギー内科
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/rheumatology/
• [Remarks] 筑波大学医学医療系 膠原病リウマチアレルギー内科
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/rheumatology/
• [Patent(Industrial Property Rights)] 関節リウマチ診断薬 (2020)
  • Inventor(s): 松本功
  • Industrial Property Rights Holder: 松本功
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas