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Multidisciplinary analysis of heterogeneity in autoimmune autonomic ganglionopathy

Research Project

Project/Area Number 19H03549
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionNippon Medical School (2021-2022)
Kumamoto University (2019-2020)

Principal Investigator

Nakane Shunya  日本医科大学, 医学部, 准教授 (70398022)

Co-Investigator(Kenkyū-buntansha) 池田 徳典  崇城大学, 薬学部, 准教授 (00613530)
佐藤 伸一  東京大学, 医学部附属病院, 教授 (20215792)
田村 直人  順天堂大学, 医学部, 教授 (20227284)
樋口 理  独立行政法人国立病院機構長崎川棚医療センター(臨床研究部), その他の研究科, 研究員(移行) (50361720)
鈴木 隆二  独立行政法人国立病院機構(相模原病院臨床研究センター), 臨床免疫研究室, 室長 (70373470)
坪井 洋人  筑波大学, 医学医療系, 准教授 (80580505)
伊原 栄吉  九州大学, 医学研究院, 准教授 (80612390)
宋 文杰  熊本大学, 大学院生命科学研究部(医), 教授 (90216573)
川上 純  長崎大学, 医歯薬学総合研究科(医学系), 教授 (90325639)
佐藤 和貴郎  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 免疫研究部, 室長 (90469990)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Keywords自己免疫性自律神経節障害 / 自律神経節 / 自己抗体 / 動物モデル / 自律神経障害 / 自律神経節アセチルコリン受容体 / 能動免疫 / 膠原病 / サルコイドーシス / 小児神経 / 自律神経外障害 / 抗自律神経節アセチルコリン受容体抗体 / 多様性
Outline of Research at the Start

自己免疫性自律神経節障害は自律神経系が免疫異常の標的となる比較的新しい疾患概念である.本症では抗自律神経節アセチルコリン受容体抗体は病原性自己抗体として病態の鍵となる役割を果たす.自己免疫性自律神経節障害は自律神経系外の症候や膠原病などの併存,小児症例が存在する.こういった「多様性」が本症の診断しにくさ,難治化につながっている.本研究では1)自己抗体の病原性検証,2)病態モデル開発,3)小児症例,膠原病症例における臨床的特徴の解析,を遂行する.
「複雑な病態と臨床像=多様性」への多角的アプローチが自己免疫性自律神経節障害の診断基準作成,治療ストラテジーの確立に貢献すると考えられる.

Outline of Final Research Achievements

As a clinical study of AAG, we analyzed the clinical picture of antibody-positive AAG. In addition, we also focused on autonomic neuropathy and gAChR antibodies in systemic diseases (collagen disease, sarcoidosis, etc.) caused by immune abnormalities. Clinical studies focused on pediatric AAG, which has a different disease profile from adult AAG, and the efficacy of immunotherapy for AAG, especially complex immunotherapy, were also reported. As a result of basic research in this project, a new animal model was successfully generated by active immunization with peptides from the extracellular region of the α3 subunit of nicotinic gAChR. The analysis of "Clinical investigation of gAChR antibody-positive frequency and autonomic neuropathy in collagen diseases" has been completed, and the paper is under preparation.

Academic Significance and Societal Importance of the Research Achievements

自己免疫性自律神経節障害は2000年に米国から提示された比較的新しい疾患概念である。我々は日本でも本症の自己抗体である自律神経節アセチルコリン受容体(gAChR)抗体の測定系を2012年に樹立・整備し、それ以来全国からの抗体測定の依頼に応えてきた(測定事業は現在は検査会社に移管)。日本のAAG症例の臨床像、治療法を本研究で明らかにすることができ、さらに非典型的な経過や症候を呈する限局型AAGや小児AAG、膠原病との併発についても臨床研究を行った。これらの蓄積は今後、日本におけるAAG診断基準策定に役立つと考える。
基礎研究では世界で初めて能動免疫モデルマウスを樹立したことが大きな成果である。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (30 results)

All 2023 2022 2021 2020 2019

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (18 results) (of which Int'l Joint Research: 1 results,  Invited: 15 results)

  • [Journal Article] Gut microbiota of Parkinson's disease in an appendectomy cohort: a preliminary study2023

    • Author(s)
      Nakahara K, Nakane S, Ishii K, Ikeda T, Ando Y.
    • Journal Title

      Sci Rep

      Volume: 13 Issue: 1 Pages: 2210-2210

    • DOI

      10.1038/s41598-023-29219-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effectiveness of treatment for 31 patients with seropositive autoimmune autonomic ganglionopathy in Japan2022

    • Author(s)
      Hayashi Toshiyuki、Nakane Shunya、Mukaino Akihiro、Higuchi Osamu、Yamakawa Makoto、Matsuo Hidenori、Kimura Kazumi
    • Journal Title

      Therapeutic Advances in Neurological Disorders

      Volume: 15

    • DOI

      10.1177/17562864221110048

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel murine model of autoimmune dysautonomia by α3 nicotinic acetylcholine receptor immunization2022

    • Author(s)
      Yamakawa M, Nakane S, Ihara E, Tawara N, Ikeda H, Igarashi Y, Komohara Y, Takamatsu K, Ikeda T, Tomita Y, Murai S, Ando Y, Mukaino A, Ogawa Y, Ueda M.
    • Journal Title

      Front Neurosci

      Volume: 16 Pages: 1006923-1006923

    • DOI

      10.3389/fnins.2022.1006923

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunotherapy for ocular myasthenia gravis: an observational study in Japan2022

    • Author(s)
      Narita Tomoko; Nakane Shunya, Nagaishi Akiko, Minami Naoya, Niino Masaaki, Kawaguchi Naoki, Murai Hiroyuki, Kira Jun-Ichi, Shimizu Jun, Iwasa Kazuo, Yoshikawa Hiroaki, Hatanaka Yuki, Sonoo Masahiro, Shimizu Yuko, Matsuo Hidenori
    • Journal Title

      Therapeutic advances in neurological disorders

      Volume: 16 Pages: 1-12

    • DOI

      10.1177/17562864231163819

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] gAChR antibodies in children and adolescents with acquired autoimmune dysautonomia in Japan.2021

    • Author(s)
      Yamakawa M, Watari M, Torii KI, Kuki I, Miharu M, Kawazu M, Mukaino A, Higuchi O, Maeda Y, Ikeda T, Takamatsu K, Tawara N, Nakahara K, Matsuo H, Ueda M, Takahashi T, Nakane S
    • Journal Title

      Ann Clin Transl Neurol.

      Volume: 8 Issue: 4 Pages: 790-799

    • DOI

      10.1002/acn3.51317

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between neurosarcoidosis with autonomic dysfunction and anti-ganglionic acetylcholine receptor antibodies.2021

    • Author(s)
      Oishi M, Mukaino A, Kunii M, Saito A, Arita Y, Koike H, Higuchi O, Maeda Y, Abiru N, Yamaguchi N, Kawano H, Tsuiki E, Tanaka T, Matsuo H, Katsuno M, Tanaka F, Tsujino A, Nakane S
    • Journal Title

      J Neurol.

      Volume: 268 Issue: 11 Pages: 4265-4279

    • DOI

      10.1007/s00415-021-10551-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology.2020

    • Author(s)
      Nakane S, Mukaino A, Ihara E, Ogawa Y.
    • Journal Title

      Immunol Med.

      Volume: 1 Issue: 2 Pages: 1-12

    • DOI

      10.1080/25785826.2020.1797319

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antibodies to the α3 subunit of the ganglionic-type nicotinic acetylcholine receptors in patients with autoimmune encephalitis.2020

    • Author(s)
      Yamakawa M, Mukaino A, Kimura A, Nagasako Y, Kitazaki Y, Maeda Y, Higuchi O, Takamatsu K, Watari M, Yoshikura N, Ikawa M, Sugimoto I, Sakurai Y, Matsuo H, Ando Y, Shimohata T, Nakane S.
    • Journal Title

      J Neuroimmunol.

      Volume: 349 Pages: 577399-577399

    • DOI

      10.1016/j.jneuroim.2020.577399

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy.2020

    • Author(s)
      Nakane S, Mukaino A, Higuchi O, Yasuhiro M, Takamatsu K, Yamakawa M, Watari M, Tawara N, Nakahara KI, Kawakami A, Matsuo H, Ando Y.
    • Journal Title

      J Autoimmun.

      Volume: 108 Pages: 102403-102403

    • DOI

      10.1016/j.jaut.2020.102403

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.2020

    • Author(s)
      Imamura M, Mukaino A, Takamatsu K, Tsuboi H, Higuchi O, Nakamura H, Abe S, Ando Y, Matsuo H, Nakamura T, Sumida T, Kawakami A, Nakane S.
    • Journal Title

      Int J Mol Sci.

      Volume: 21 Issue: 4 Pages: 1332-1332

    • DOI

      10.3390/ijms21041332

    • NAID

      120007132699

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detecting gastrointestinal manifestations in patients with systemic sclerosis using anti-gAChR antibodies.2020

    • Author(s)
      Nakane S, Umeda M, Kawashiri SY, Mukaino A, Ichinose K, Higuchi O, Maeda Y, Nakamura H, Matsuo H, Kawakami A.
    • Journal Title

      Arthritis Res Ther.

      Volume: 22 Issue: 1 Pages: 32-32

    • DOI

      10.1186/s13075-020-2128-z

    • NAID

      120006988287

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autoimmune autonomic ganglionopathy2019

    • Author(s)
      中根俊成
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 59 Issue: 12 Pages: 783-790

    • DOI

      10.5692/clinicalneurol.cn-001354

    • NAID

      130007772724

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 視神経脊髄炎スペクトラム障害 =病態・臨床に基づいたアプローチ=2022

    • Author(s)
      中根俊成
    • Organizer
      第31回日本脳ドック学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 自律神経ニューロパチーにおける自己抗体2022

    • Author(s)
      中根俊成
    • Organizer
      第33回日本末梢神経学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 自己免疫性自律神経節障害2022

    • Author(s)
      中根俊成
    • Organizer
      第34回日本神経免疫学学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 重症筋無力症におけるアフェレシス2022

    • Author(s)
      中根俊成
    • Organizer
      第43回日本アフェレシス学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 自己免疫性自律神経節障害pdate2021

    • Author(s)
      中根俊成
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 自己抗体から考える重症筋無力症の病態と診療2021

    • Author(s)
      中根俊成
    • Organizer
      第29回日本神経学会中国・四国地区生涯教育講演会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Research on AAG2021

    • Author(s)
      中根俊成
    • Organizer
      第74回日本自律神経学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Immunization of mice with α3 nicotinic acetylcholine receptor induces autonomic dysfunction2021

    • Author(s)
      中根俊成
    • Organizer
      32ND INTERNATIONAL SYMPOSIUM ON THE AUTONOMIC NERVOUS SYSTEM
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 小児における自己免疫性自律神経節障害の臨床的特徴2021

    • Author(s)
      中根俊成
    • Organizer
      48回日本臨床免疫学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] VGKC複合体抗体関連疾患、スティッフパーソン症候群、自己免疫性自律神経節障害2021

    • Author(s)
      中根俊成
    • Organizer
      第41回日本アフェレシス学会学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 自己免疫性自律神経節障害の過去・現在・未来2021

    • Author(s)
      中根俊成
    • Organizer
      第38回日本神経治療学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 神経筋接合部疾患における自己抗体測定2021

    • Author(s)
      中根俊成
    • Organizer
      第50回日本臨床神経生理学会学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 自己免疫性自律神経節障害 =今、われわれがわかっていること=2020

    • Author(s)
      中根俊成
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] The ganglionic AChR autoantibodies in autoimmune autonomic ganglionopathy: An update on diagnosis and treatment2019

    • Author(s)
      Nakane S
    • Organizer
      60th Annual Meeting of the Japanese Society of Neurology
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] パーキンソン病における 自己免疫基盤を考える2019

    • Author(s)
      中根俊成
    • Organizer
      第13回パーキンソン病・運動障害疾患コングレス
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] パーキンソニズムを呈した抗自律神経節アセチルコリン受容体抗体陽性症例2019

    • Author(s)
      中根俊成
    • Organizer
      第31回日本神経免疫学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 広がりゆく自己免疫性自律神経節障害の概念2019

    • Author(s)
      中根俊成
    • Organizer
      第47回日本臨床免疫学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 自己免疫性自律神経節障害 =免疫系の標的としての自律神経系=2019

    • Author(s)
      中根俊成
    • Organizer
      第72回日本自律神経学会総会
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2024-01-30  

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