Involvement of ischemic tissue injury in inflammatory demyelinating disease and its therapeutic application

• Project/Area Number: 17K16108
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Takai Yoshiki 東北大学, 大学病院, 医員 (40725743)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 炎症性脱髄疾患 / 腫瘍様炎症性脱髄疾患 / 自然免疫 / TRL / Tenascin / 脳虚血 / HIF-1 / Tenascin-C / 虚血 / TDD / Balo / NMO / DAMPs / HMGB-1 / 虚血性組織障害 / 多発性硬化症 / 視神経脊髄炎 / Balo病

Outline of Final Research Achievements

The purpose of this study is to elucidate the pathophysiology of inflammatory demyelinating diseases in the central nervous system.We immunohistochemically analysed biopsied brain tissues from 23 patients with inflammatory demyelinating diseases.The brain biopsies were performed between April 1998 and March 2018.
Among them, four of which showed extensive necrosis in the center of the demyelinating lesions. Interestingly, in the vessels located at the boundary between the necrotic site and the demyelinating lesion,expression of Toll-like receptor 4 on the vascular endothelium was enhanced, and prominant deposition of Tenascin-C was seen at enlarged perivascular space.These characteristic findings were not found in any other inflammatory demyelinating diseases such as multiple sclerosis, neuromyelitis optica and acute disseminated encephalomyelitis.

Academic Significance and Societal Importance of the Research Achievements

中枢神経における炎症性脱髄疾患は、一般的に獲得免疫の異常により生じる疾患と考えられている。本研究で得られた知見は、これまで病態が未解明だった一部の類縁疾患において、自然免疫に重要と考えられるToll-like receptorの発現亢進が血管周囲で生じ、その活性化に影響するとされる細胞外マトリックスが血管周囲腔に顕著に沈着するという、既知の疾患概念と大きく異なる病態が存在していることを示唆しており、新たな疾患概念を提唱しうる極めて重要な発見と考えられた。

Research Products

• [Journal Article] Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study (2020)
  • Author(s): Takai Y, Misu M, Kaneko K, Chihara N, Narikawa K, Tsuchida S, Nishida H, Komori T, Seki M, Komatsu T, Nakamagoe K, Ikeda T, Yoshida M, Takahashi T, Ono H, Nishiyama S, Kuroda H, Nakashima I, Suzuki H, Bradl M, Lassmann H, Fujihara K, Aoki M
  • Journal Title: Brain Volume: In press
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic feature of MOG antibody-associated disease. (2019)
  • Author(s): Y Takai,T Misu, K Kaneko, N Chihara, K Narikawa, S Tsuchida, H Nishida, T Komori, M Seki, T Komatsu T, K Nakamagoe, T Ikeda, M Yoshida, T Takahashi, H Ono, S Nishiyama, H Kuroda, I Nakashima, H Suzuki, M Bradl, H Lassmann, K Fujihara, M Aoki.
  • Organizer: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (Stockholm, Sweden)
  • Int'l Joint Research
• [Presentation] The Expression of IL-6 in The Central Nervous Tissue of Neuromyelitis Optica Spectrum Disorders (2019)
  • Author(s): Y Takai, T Misu, C Namatame, Y Mastumoto, H Ono, K Kaneko, T Takahashi, S Nishiyama, H Kuroda, M Aoki, K Fujihara
  • Organizer: 12th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (Singapore)
  • Int'l Joint Research
• [Presentation] Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study (2019)
  • Author(s): Y Takai,T Misu, K Kaneko, N Chihara, K Narikawa, S Tsuchida, H Nishida, T Komori, M Seki, T Komatsu T, K Nakamagoe, T Ikeda, M Yoshida, T Takahashi, H Ono, S Nishiyama, H Kuroda, I Nakashima, H Suzuki, M Bradl, H Lassmann, K Fujihara, M Aoki.
  • Organizer: 第60回日本神経学会学術大会（大阪）
• [Presentation] 視神経脊髄炎中枢組織障害に対するIL-6の影響に関する病理学的検討 (2019)
  • Author(s): 高井 良樹, 三須 建郎, 松本 勇貴, 生田目 千尋, 小野 紘彦, 西山 修平, 黒田 宙, 藤原 一男, 青木 正志
  • Organizer: 第31回日本神経免疫学会学術集会（千葉）
• [Presentation] Perivenous inflammatory demyelination is the prominent pathology in myelin oligodendrocyte glycoprotein antibody-associated disease. (2018)
  • Author(s): Takai Y, Misu T, Kaneko K, Chihara N, Narikawa K, Tsuchida S, Nishida H, Takahashi T, Aoki M, Fujihara K
  • Organizer: 19th International Congress of Neuropathology (Tokyo, Japan)
• [Presentation] Perivenous inflammatory demyelination with CD4-dominat T cell infiltration is prominent in myelin oligodendrocyte glycoprotein antibody-associated disease. (2018)
  • Author(s): Takai Y, Misu T, Kaneko K, Chihara N, Narikawa K, Tsuchida S, Nishida H, Takahashi T, Aoki M, Fujihara K
  • Organizer: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (Berlin, Germany)
  • Int'l Joint Research
• [Presentation] Perivenous inflammatory demyelination with myelin oligodendrocyte glycoprotein (MOG)-dominant myelin loss and CD4-dominant T cell infiltration is prominent in MOG antibody-associated disease. (2018)
  • Author(s): Takai Y, Misu T, Kaneko K, Chihara N, Narikawa K, Tsuchida S, Nishida H, Takahashi T, Aoki M, Fujihara K
  • Organizer: 11th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (Sydney, Australia)
  • Int'l Joint Research
• [Presentation] The staging of astrocytopathy in neuromyelitis optica spectrum disorders with aquaporin 4-IgG (2017)
  • Author(s): Y. Takai, T. Misu, S. Nishiyama, H. Kuroda, R. Ogawa, K. Kaneko, T. Takahashi, I. Nakashima, Suzuki H, K. Fujihara, M. Aoki
  • Organizer: 33rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (London, United Kingdom)
  • Int'l Joint Research