自己抗体により規定される「4つの皮膚筋炎」病型の病態解明と特異的治療法の開発

• Project/Area Number: 23K21438
• Project/Area Number (Other): 21H02942 (2021-2023)
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund (2024); Single-year Grants (2021-2023)
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Osaka University
• Principal Investigator: 藤本 学 大阪大学, 大学院医学系研究科, 教授 (90272591)
• Project Period (FY): 2021-04-01 – 2026-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2025: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2024: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2023: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 自己免疫 / 皮膚免疫 / 膠原病 / 疾患モデル / 免疫

Outline of Research at the Start

皮膚筋炎は、皮膚および筋の炎症性変化を主徴とする自己免疫疾患であり、治療法が確立していない難病である。皮膚筋炎の概念は過去約10年 の間に飛躍的に進歩し、自己抗体により病型分類する考え方が主流となってきた。本研究は、4つの皮膚筋炎主要自己抗体、抗ARS抗体、抗MDA5抗体、抗TIF1抗体、抗Mi-2抗体の抗原免疫により誘導される筋炎・間質性肺炎マウスモデルおよびヒト皮膚筋炎患者検体の両方を用いて、「4つの自己抗体により規定 される皮膚筋炎」のそれぞれの病型について、病因・病態の探索、皮膚病変を主たる対象とした疾患パスウェイ解析、個別特異的治療法の探索と確立 の3つの面から研究を行う。

Outline of Annual Research Achievements

抗melanoma differentiation-associated gene 5 (MDA5) 抗体陽性皮膚筋炎は、予後不良の急速進行性間質性肺疾患の合併が特徴である。MDA5リコンビナントタンパクをアジュバントとともに免疫してからPoly(I:C)の吸入により間質性肺炎を誘発するマウスモデルを作成し、その発症機序について検討を行った。MDA5タンパクをアジュバントとともに免疫した場合には、アジュバント単独に比べて有意に重度の間質性肺疾患が惹起され、これはCD8T細胞ではなくCD4 T細胞除去により軽減し、またその病態にはIL-6の関与が重要であることが示された。また、ヒトにおける皮膚筋炎患者（抗transcriptional intermeidary factor 1 gamma抗体陽性例）の末梢血、腫瘍浸潤、および皮膚浸潤T細胞/B細胞のクローナリティについても解析を進め、そのリンパ球の表現型について解析を行った。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

新たなマウスモデルが確立され、またヒトにおける解析も進んでいるため

Strategy for Future Research Activity

マウスモデルを用いてさらに病態メカニズムの解析を進めるとともに、ヒトにおけるリンパ球のシングルセル解析を症例を増やして行う。

Research Products

• [Journal Article] Muscle pathology of antisynthetase syndrome according to antibody subtypes (2023)
  • Author(s): Tanboon Jantima、Inoue Michio、Hirakawa Shinya、Tachimori Hisateru、Hayashi Shinichiro、Noguchi Satoru、Okiyama Naoko、Fujimoto Manabu、Suzuki Shigeaki、Nishino Ichizo
  • Journal Title: Brain Pathology Volume: 33 Issue: 4
  • DOI: 10.1111/bpa.13155
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 2 Cite Share International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative. (2023)
  • Author(s): Oldroyd AGS, Callen JP, Chinoy H, Chung L, Fiorentino D, Gordon P, Machado PM, McHugh N, Selva-O'Callaghan A, Schmidt J, Tansley SL, Vleugels RA, Werth VP; International Myositis Assessment and Clinical Studies Group Cancer Screening Expert Group; Aggarwal R.
  • Journal Title: Nat Rev Rheumatol. Volume: 19 Issue: 12 Pages: 805-817
  • DOI: 10.1038/s41584-023-01045-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Combination of Autoantibodies Predicts the Fate of Cancer-Associated Dermatomyositis (2023)
  • Author(s): Fujimoto M.
  • Journal Title: Arthritis Rheumatol. Volume: 75 Issue: 7 Pages: 1085-1087
  • DOI: 10.1002/art.42472
  • Peer Reviewed
• [Journal Article] 59.Age distribution and prevalence in different age groups of four myositis-specific autoantibodies, including anti-ARS, anti-MDA5, anti-Mi-2, and anti-TIF1γ antibodies (2023)
  • Author(s): Ueda-Hayakawa I, Tonomura K, Maekawa A, Kaneda E, Arase N, M Fujimoto M
  • Journal Title: J Dermatol. Volume: - Issue: 8 Pages: 1058-1062
  • DOI: 10.1111/1346-8138.16772
  • Peer Reviewed
• [Journal Article] Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies. (2022)
  • Author(s): [Noriko Arase,Hideaki Tsuji,Hyota Takamatsu,Hui Jin,Hachiro Konaka,Yasuhito Hamaguchi,Kyoko Tonomura,Yorihisa Kotobuki,Ikuko Ueda-Hayakawa,Sumiko Matsuoka,Toru Hirano,Hideki Yorifuji,Hiroyuki Murota,Koichiro Ohmura,Ran Nakashima,Tomoharu Sato,Atsushi Kumanogoh,Ichiro Katayama,Hisashi Arase,Manabu Fujimoto]
  • Journal Title: Journal of autoimmunity Volume: 126 Pages: 102774-102774
  • DOI: 10.1016/j.jaut.2021.102774
  • Peer Reviewed / Open Access
• [Journal Article] Dermatomyositis (2021)
  • Author(s): Tanboon Jantima、Inoue Michio、Saito Yoshihiko、Tachimori Hisateru、Hayashi Shinichiro、Noguchi Satoru、Okiyama Naoko、Fujimoto Manabu、Nishino Ichizo
  • Journal Title: Neurology Volume: 98 Issue: 7
  • DOI: 10.1212/wnl.0000000000013176
  • Peer Reviewed / Open Access
• [Journal Article] Idiopathic inflammatory myopathies. (2021)
  • Author(s): Lundberg IE, Fujimoto M, Vencovsky J, Aggarwal R, Holmqvist M, Christopher-Stine L, Mammen AL, Miller FW.
  • Journal Title: Nat Rev Dis Primers Volume: 7 Issue: 1 Pages: 86-86
  • DOI: 10.1038/s41572-021-00321-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ can result in experimental myositis. (2021)
  • Author(s): Okiyama N, Ichimura Y, Shobo M, Tanaka R, Kubota N, Saito A, Ishitsuka Y, Watanabe R, Fujisawa Y, Nakamura Y, Murakami A, Kayama H, Takeda K, Fujimoto M
  • Journal Title: Ann Rheum Dis Volume: N.A. Issue: 9 Pages: 1201-1208
  • DOI: 10.1136/annrheumdis-2020-218661
  • Peer Reviewed
• [Journal Article] Clinical and laboratory parameters predicting cancer in dermatomyositis patients with anti-TIF1γ antibodies (2021)
  • Author(s): Ly NTM, Ma N, Ueda-Hayakawa I, Nguyen CTH, Anada R, Okamoto H, Fujimoto M.
  • Journal Title: J Dermatol Sci Volume: 104 Issue: 3 Pages: 177-184
  • DOI: 10.1016/j.jdermsci.2021.10.003
  • Peer Reviewed
• [Journal Article] Myxovirus resistance protein 1-expressing fatal myocarditis in a patient with anti-MDA5 antibody-positive dermatomyositis. (2021)
  • Author(s): [Rika Sakamoto,Yorihisa Kotobuki,Saki Iga,Satoshi Nojima,Rikako Deno,Yuma Hanaoka,Kyoko Tonomura,Eiji Kiyohara,Yukinobu Nakagawa,Ikuko Ueda-Hayakawa,Noriko Arase,Manabu Fujimoto]
  • Journal Title: Rheumatology (Oxford, England) Volume: 60 Issue: 12 Pages: e450-e452
  • DOI: 10.1093/rheumatology/keab637
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of four myositis-specific autoantibodies with regulatory-approved testing in Japan: A Japanese multi-centre adult myositis patients' cohort (2021)
  • Author(s): Ueda-Hayakawa I, Fujimoto M, Sato S, Murakami A, Kawakami A, Mishima M, Seishima M, Suda T, Takehara K, Mimori T, Kuwana M.
  • Journal Title: J Dermatol Sci Volume: 103 Issue: 1 Pages: 53-56
  • DOI: 10.1016/j.jdermsci.2021.05.005
  • Peer Reviewed