Gene expression profiling of inflammatory myopathy in correlation with autoantibodies

• Project/Area Number: 15K09347
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: Shimizu Jun 東京大学, 医学部附属病院, 届出診療医・客員研究員 (40260492)
• Co-Investigator(Kenkyū-buntansha): 後藤 順 国際医療福祉大学, 医学部, 教授 (10211252) ; 石浦 浩之 東京大学, 医学部附属病院, 助教 (40632849)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 炎症性筋疾患 / 発現解析 / 筋炎自己抗体 / 生検筋 / 次世代シーケンサー / 皮膚筋炎 / 筋炎 / RNA発現解析 / 病態機序

Outline of Final Research Achievements

We performed mRNA microarray analysis of biopsied muscles from patients with IIMs and analyzed the relation with myositis specific antibodies (MSAs). In analysis of muscles with perifascicular atrophy, specific sets of mRNAs allow for molecular classification of patients with anti-Jo1 (n=4), -TIF1γ (n=5), and -Mi-2 (n=5) antibodies. In analysis of muscles with early pathological findings with anti-Jo1(n=4), -TIF1γ(n=4), and -MDA5 (n=4) antibodies, a total of 1705 mRNAs were significantly expressed (fold change>3, p<0.05). Pathway analysis for the 192 mRNAs commonly significantly changed in three groups were Toll-like and NOD-like receptor pathways. In analysis of mRNAs with significant changes, specific sets of mRNAs allow for molecular classification of patients with MSAs, respectively. Our findings showed that there are characteristic mRNAs expression profiles in relation with the types of MSAs even in muscles with mild pathological changes.

Academic Significance and Societal Importance of the Research Achievements

筋炎特異抗体と特徴的な筋病理所見の関係検討や、筋炎特異抗体ごとの筋組織mRNA発現プロファイル解析は過去に充分になされていない。本研究では多数例を用い網羅的に統計的に検討した点、組織所見を対応させた上でmRNA発現プロファイル解析を行った点で意義がある。病理変化の初期より抗体ごとに特徴的なmRNAの変化が存在したことは、これらの変化が組織変化の結果ではなく原因であることを示す。本検討は病理変化の初期のmRNAの変化を筋炎特異抗体ごとに捉えることで筋炎亜群ごとの最も初期の病態解析が可能であることを示した。ステロイドなどの非特異的な治療とは異なる病態特異的な治療方法の開発に繋がることが期待される。

Research Products

• [Journal Article] Inflammatory myopathy with myasthenia gravis (2018)
  • Author(s): Uchio Naohiro、Taira Kenichiro、Ikenaga Chiseko、Kadoya Masato、Unuma Atsushi、Yoshida Kenji、Nakatani-Enomoto Setsu、Hatanaka Yuki、Sakurai Yasuhisa、Shiio Yasushi、Kaida Kenichi、Kubota Akatsuki、Toda Tatsushi、Shimizu Jun
  • Journal Title: Neurology - Neuroimmunology Neuroinflammation Volume: 6 Issue: 2
  • DOI: 10.1212/nxi.0000000000000535
  • Peer Reviewed / Open Access
• [Journal Article] Granulomatous myositis induced by anti-PD-1 monoclonal antibodies (2018)
  • Author(s): Uchio Naohiro、Taira Kenichiro、Ikenaga Chiseko、Unuma Atsushi、Kadoya Masato、Kubota Akatsuki、Toda Tatsushi、Shimizu Jun
  • Journal Title: Neurology - Neuroimmunology Neuroinflammation Volume: 5 Issue: 4
  • DOI: 10.1212/nxi.0000000000000464
  • Peer Reviewed / Open Access
• [Journal Article] A Homozygous LAMA2 Mutation of c.818G>A Caused Partial Merosin Deficiency in a Japanese patient (2018)
  • Author(s): Kubota A, Ishiura H, Mitsui J, Sakuishi K, Iwata A, Yamamoto T, Nishino I, Tsuji S, Shimizu J
  • Journal Title: Intern Med Volume: 15;57(6) Pages: 877-882
  • NAID: 130006507413
• [Journal Article] Identification and segmentation of myelinated nerve fibers in a cross-sectional optical microscopic image using a deep learning model (2017)
  • Author(s): Naito Tatsuhiko、Nagashima Yu、Taira Kenichiro、Uchio Naohiro、Tsuji Shoji、Shimizu Jun
  • Journal Title: J Neurosci Methods Volume: 291 Pages: 141-149
  • DOI: 10.1016/j.jneumeth.2017.08.014
• [Journal Article] Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia (2017)
  • Author(s): Kurihara Masanori、Ishiura Hiroyuki、Sasaki Takuya、Otsuka Juuri、Hayashi Toshihiro、Terao Yasuo、Matsukawa Takashi、Mitsui Jun、Kaneko Juntaro、Nishiyama Kazutoshi、Doi Koichiro、Yoshimura Jun、Morishita Shinichi、Shimizu Jun、Tsuji Shoji
  • Journal Title: Cerebellum Volume: 17 Issue: 2 Pages: 237-242
  • DOI: 10.1007/s12311-017-0883-4
  • Peer Reviewed
• [Journal Article] Low back pain due to superior cluneal nerve entrapment: A clinicopathologic study (2017)
  • Author(s): Kim Kyongsong、Shimizu Jun、Isu Toyohiko、Inoue Kiyoharu、Chiba Yasuhiro、Iwamoto Naotaka、Morimoto Daijiro、Isobe Masanori、Morita Akio
  • Journal Title: Muscle Nerve Volume: Nov 3 Issue: 5 Pages: 1-7
  • DOI: 10.1002/mus.26007
  • Peer Reviewed
• [Journal Article] Partial duplication of DHH causes minifascicular neuropathy (2017)
  • Author(s): Sato Naoko Saito、Maekawa Risa、Ishiura Hiroyuki、Mitsui Jun、Naruse Hiroya、Tokushige Shin-ichi、Sugie Kazuma、Tate Genshu、Shimizu Jun、Goto Jun、Tsuji Shoji、Shiio Yasushi
  • Journal Title: Ann Clin Transl Neurol Volume: 4 Issue: 6 Pages: 415-421
  • DOI: 10.1002/acn3.417
• [Journal Article] Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology (2017)
  • Author(s): Ikenaga C, Kubota A, Kadoya M, Taira K, Uchio N, Hida A, Maeda MH, Nagashima Y, Ishiura H, Kaida K, Goto J, Tsuji S, Shimizu J
  • Journal Title: Neurology Volume: 5;89(10) Issue: 10 Pages: 1060-1068
  • DOI: 10.1212/wnl.0000000000004333
• [Journal Article] Cancer-association as a risk factor for anti-HMGCR antibody-positive myopathy (2016)
  • Author(s): Kadoya M, Hida A, Maeda M, Taira K, Ikenaga C, Uchio N, Kubota A, Kaida K, Miwa Y, Kurasawa K, Shimada H, Sonoo M, Chiba A, Shiio Y, Uesaka Y, Sakurai Y, Izumi T, Inoue M, Kwak S, Tsuji S, Shimizu
  • Journal Title: Neurology Volume: 3(6):e290, Issue: 6 Pages: 1-10
  • DOI: 10.1212/nxi.0000000000000290
  • Peer Reviewed / Open Access
• [Journal Article] Anti-TIF1-gamma antibody and cancer-associated myositis: A clinicohistopathologic study (2016)
  • Author(s): Hida A, Yamashita T, et. al. Tsuji S, Kwak S, Mimori T, Shimizu J
  • Journal Title: Neurology Volume: 87 Pages: 299-308
  • Peer Reviewed / Open Access
• [Journal Article] Sporadic late-onset nemaline myopathy as a rare cause of slowly progressive muscle weakness with young adult onset (2015)
  • Author(s): Maeda MH, Ohta H, Izutsu K, Shimizu J, Uesaka Y
  • Journal Title: Muscle Nerve Volume: 00 Issue: 5 Pages: 00-00
  • DOI: 10.1002/mus.24509
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] MYOPATHY PATHOLOGY (Lecture) (2017)
  • Author(s): Shimizu J
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research / Invited
• [Presentation] Usefulness of cytoplasmic 5'- nucleotidase 1A autoantibodies for diagnosing patients with inclusion body myositis (2017)
  • Author(s): Chiseko Ikenaga, Masato Kadoya, Naohiro Uchio, Kenichiro Taira, Akatsuki Kubota, Shoji Tsuji, Jun Shimizu
  • Organizer: 22ND INTERNATIONAL CONGRESS OF THE WMS
• [Presentation] The cut-off levels of serum creatine kinase as a diagnostic marker for myopathy with anti-SRP or -HMGCR autoantibodies positive (2017)
  • Author(s): Kenichiro Taira, Masato Kadoya, Naohiro Uchio, Astushi Unuma, Akatsuki Kubota, Chiseko Ikenaga,Shoji Tsuji1 Tsuneyo Mimori, and Jun Shimizu
  • Organizer: XXIII World Congress of Neurology
• [Presentation] Clinicopathological Features of Anti-NT5c1A Positive Patients in the Group of Myositis Patients with CD8-MHC-1 Complex Pathology (2016)
  • Author(s): Chiseko Ikenaga, Masato Kadoya, Meiko Maeda, Shoji Tsuji, Jun Shimizu
  • Organizer: The American Academy of Neurology 68th Annual Meeting
  • Place of Presentation: Vancouver, BC, Canada
  • Year and Date: 2016-04-15
  • Int'l Joint Research
• [Presentation] Clinicopathological Features of Anti-NT5c1A Positive Patients in the Group of Myositis Patients with CD8-MHC-1 Complex Pathology (2016)
  • Author(s): Chiseko Ikenaga, Masato Kadoya, Meiko Maeda, Shoji Tsuji, Jun Shimizu
  • Organizer: The American Academy of Neurolog, 68th Annual Meeting
  • Place of Presentation: Vancouver, BC, Canada
  • Year and Date: 2016-04-15
  • Int'l Joint Research
• [Presentation] Clinicopathological features of patients with neuromuscular disease showing CD8-MHC-1 complex pathology&#8232; (2015)
  • Author(s): Chiseko Ikenaga, Meiko Maeda, Shoji Tsuji, Jun Shimizu&#8232;
  • Organizer: American Academy of Neurology 67th Annual Meeting
  • Place of Presentation: Washington, DC, U.S.A
  • Year and Date: 2015-04-18
  • Int'l Joint Research