Analysis of the pathomechanism of secondary demyelination in primary astrocytopathy model

• Project/Area Number: 24591247
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: MISU Tatsuro 東北大学, 医学(系)研究科(研究院), 助教 (00396491)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 神経免疫 / 脱髄 / アストロサイト / アクアポリン / 視神経脊髄炎 / アクアポリン4 / アクアポリン４ / 国際研究者交流(オーストリア）

Outline of Final Research Achievements

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease by anti-aquaporin 4 (AQP4) antibody mainly targeting against astrocyte foot processes in the central nervous system (CNS). However, the mechanism of demyelination is not well resolved.
In this project, we have studied the mechanism of astrocytopathy and demyelination by passive transfer model of AQP4 antibody on rodent experimental encephalomyelitis. This model is featured by highly reproducible and typical astrocytopathy lesion like post-mortem cases of NMO. It is revealed that demyelination is secondarily produced after the induction of astrocytopathy lesion, and the lesion development is higly associated with infiltration of inflammatory cells, especially neutrophil.

Research Products

• [Journal Article] Editorial commentary: MOG-IgG serological status matters in paediatric ADEM (2015)
  • Author(s): Misu T, Sato D, Nakashima I, Fujihara K
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 86 Issue: 3 Pages: 242-242
  • DOI: 10.1136/jnnp-2014-308723
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A case of pathology-proven neuromyelitis optica spectrum disorder with Sjögren syndrome manifesting aphasia and apraxia due to a localized cerebral white matter lesion. (2014)
  • Author(s): Sawada J, Orimoto R, Misu T, Katayama T, Aizawa H, Asanome A, Takahashi T, Saito T, Arei R, Kamada K, Miyokawa N, Takahashi T, Fujihara K, Hasebe N.
  • Journal Title: Mult Scler Volume: 20 Issue: 10 Pages: 1413-6
  • DOI: 10.1177/1352458514540834
  • NAID: 120005511013
  • Peer Reviewed
• [Journal Article] Pain- prevalence, pathogenesis and therapy in neuromyelitis optica (2014)
  • Author(s): Bradl M, Kanamori Y, Nakashima I, Misu T, Fujihara K, Lassmann H, Sandkuhler J
  • Journal Title: Nat Rev Neurol Volume: 10 Issue: 9 Pages: 529-536
  • DOI: 10.1038/nrneurol.2014.129
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Audiological evidence of therapeutic effect of steroid treatment in neuromyelitis optica with hearing loss. (2014)
  • Author(s): Takanashi Y, Misu T, Oda K, Miyazaki H, Yahata I, Hidaka H, Fujihara K, Kawase T, Kobayashi T, Katori Y.
  • Journal Title: J Clin Neurosci. Volume: 21 Issue: 12 Pages: 2249-2251
  • DOI: 10.1016/j.jocn.2014.04.019
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid aquaporin-4 antibody levels in neuromyelitis optica attacks (2014)
  • Author(s): Sato DK, Callegaro D, MD, PhD2; Jorge FMdH, Nakashima I, Nishiyama S, Takahashi T, Simm RF, Apostolos-Pereira SL, Misu T, Steinman L, Aoki M, Fujihara K
  • Journal Title: Ann Neurol Volume: 76 Issue: 2 Pages: 305-309
  • DOI: 10.1002/ana.24208
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-N-methyl-aspartate receptor encephalitis with multiphasic demyelination (2014)
  • Author(s): Kaneko K, Sato, DK, Misu T Kurosawa K, Nakashima I, Fujihara K, Aoki M
  • Journal Title: Ann Neurol Volume: 76 Issue: 3 Pages: 462-464
  • DOI: 10.1002/ana.24224
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aquaporin-4 antibody-positive myelitis initially biopsied due to suspected spinal cord tumors: diagnostic considerations (2014)
  • Author(s): 3. Sato DK
  • Journal Title: Mult Scler Volume: 20 Issue: 5 Pages: 621-626
  • DOI: 10.1177/1352458513505350
  • Peer Reviewed
• [Journal Article] The pathology of an autoimmune astrocytopathy: lessons learned from neuromylitis optia (2014)
  • Author(s): 15. Lucchinetti CF
  • Journal Title: Brain Pathol Volume: 24 Issue: 1 Pages: 83-97
  • DOI: 10.1111/bpa.12099
  • Peer Reviewed
• [Journal Article] Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders (2014)
  • Author(s): 5. Sato DK
  • Journal Title: Neurology Volume: 82 Issue: 6 Pages: 474-481
  • DOI: 10.1212/wnl.0000000000000101
  • Peer Reviewed
• [Journal Article] Presence of sixdifferent lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica (2013)
  • Author(s): Misu T, Hoftberger R, Fujihara K, Wimmer I, Takai Y, Nishiyama S, Nakashima I, Konno H, Bradl M, Garzuly F, Itoyama Y, Aoki M, Lassmann H.
  • Journal Title: Acta Neuropathol Volume: 125 Issue: 6 Pages: 815-827
  • DOI: 10.1007/s00401-013-1116-7
  • Peer Reviewed
• [Journal Article] Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders (2013)
  • Author(s): Sato DK, Nakashima I, Takahashi T, Misu T, Waters P, Kuroda H, Nishiyama S, Suzuki C, Takai Y, Fujihara K, Itoyama Y, Aoki M.
  • Journal Title: Neurology Volume: 80 Issue: 24 Pages: 2210-2216
  • DOI: 10.1212/wnl.0b013e318296ea08
  • Peer Reviewed
• [Journal Article] A Novel Monoclonal Antibody Against the C-Terminal Region of Aquaporin-4 (2013)
  • Author(s): 1. Ramadhanti J
  • Journal Title: Monoclon Antib Immunodiagn Immunother Volume: 32 Issue: 4 Pages: 270-276
  • DOI: 10.1089/mab.2013.0007
  • Peer Reviewed
• [Journal Article] Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats. (2013)
  • Author(s): Kitic M, Hochmeister S, Wimmer I, Bauer J, Misu T, Mader S, Reindl M, Fujihara K, Lassmann H, Bradl M.
  • Journal Title: Acta Neuropathol Commun. Volume: 1 Issue: 1 Pages: 5-5
  • DOI: 10.1186/2051-5960-1-5
  • Peer Reviewed
• [Journal Article] T cell-activation in neuromyelitis optica lesions plays a role in their formation (2013)
  • Author(s): 6. Pohl M
  • Journal Title: Acta Neuropathol Commun Volume: 1 Issue: 1 Pages: 85-85
  • DOI: 10.1186/2051-5960-1-85
  • Peer Reviewed
• [Journal Article] Pathological study of subacute autoimmune encephalopathy with anti-AQP4 antibodies in a pregnant woman. (2012)
  • Author(s): Yaguchi H, Yabe I, Takai Y, Misu T, et al.
  • Journal Title: Mult Scler Volume: 18 Issue: 5 Pages: 683-687
  • DOI: 10.1177/1352458511422928
  • Peer Reviewed
• [Journal Article] Recurrent hypogeusia in a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (2012)
  • Author(s): Kawaguchi, N. Sugeno, N. Endo, K. Miura, E. Misu, T. Nakashima, I. Itoyama, Y.
  • Journal Title: Journal of clinical neuroscience Volume: 19 Issue: 4 Pages: 604-605
  • DOI: 10.1016/j.jocn.2011.06.027
  • Peer Reviewed
• [Journal Article] Biomarkers in neuromyelitits optica (2012)
  • Author(s): Misu T, Takahashi T, Nakashima I, Fujihara K
  • Journal Title: Brain Nerve Volume: 64 Pages: 525-535
  • Peer Reviewed
• [Journal Article] Prognostic factors and disease course in 106 aquaporin-4 antibody-positive NMOSD patients from the United Kingdom and Japan (2012)
  • Author(s): Kitley J
  • Journal Title: Brain Volume: － Issue: 6 Pages: 1834-1849
  • DOI: 10.1093/brain/aws109
  • Peer Reviewed
• [Journal Article] A case of recurrent encephalomyelitis associated with eosinophilia in CSF. (2012)
  • Author(s): Suzuki J, Sugeno N, Nishiyama S, Kaneko K, Misu T, et al.
  • Journal Title: Rinsho Shinkeigaku Volume: 52 Pages: 571-575
  • NAID: 130004921058
  • Peer Reviewed
• [Journal Article] Neutralizing antibodies are associated with a reduction of interferon-B efficacy during the treatement of Japanese multiple sclerosis patients. (2012)
  • Author(s): Sato DK, Nakashima I, Fukazawa T, Shimizu Y, Tomizawa Y, Yokoyama K, Misu T, et al.
  • Journal Title: Tohoku J Exp Med Volume: 228 Pages: 85-92
  • Peer Reviewed
• [Journal Article] Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica (2012)
  • Author(s): Kuroda H
  • Journal Title: J Neuroimmunol Volume: 254 Issue: 1-2 Pages: 178-182
  • DOI: 10.1016/j.jneuroim.2012.09.002
  • Peer Reviewed
• [Journal Article] Two cases of lumbosacral myeloradiculitis with anti-aquaporin-4 antibody (2012)
  • Author(s): Takai Y
  • Journal Title: Neurology Volume: 79 Issue: 17 Pages: 1826-1828
  • DOI: 10.1212/wnl.0b013e3182703ff7
  • Peer Reviewed
• [Journal Article] Two cases of elderly-onset hereditary neuropath with liability to pressure palsy manifesting bilateral peroneal nerve palsies. (2012)
  • Author(s): Kawaguchi N, Suzuki N, Tateyama M, Takai Y, Misu T, et al.
  • Journal Title: Case Rep Neurol Volume: 4 Issue: 3 Pages: 149-155
  • DOI: 10.1159/000342132
  • Peer Reviewed
• [Presentation] 患者血清NMO-IgGを用いたNMOモデルラット作成の試み (2014)
  • Author(s): 黒澤和大, 三須建郎, 高橋利幸, 中島一郎, 藤原一男, 青木正志
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 金沢歌劇座（金沢）
  • Year and Date: 2014-09-04 – 2014-09-06
• [Presentation] グリア細胞から見たMS/NMO (2014)
  • Author(s): 三須建郎
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 金沢歌劇座（金沢）
  • Year and Date: 2014-09-04 – 2014-09-06
  • Invited
• [Presentation] 患者血清NMO-IgGを用いたNMOモデルラット作成の試み (2014)
  • Author(s): 黒澤和大, 三須建郎, 高橋利幸, 中島一郎, 藤原一男, 青木正志
  • Organizer: 日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] NMO病変の多様性 (2014)
  • Author(s): 三須建郎
  • Organizer: 日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07
  • Invited
• [Presentation] アクアポリン4関連アストロサイトパチー病変とアクアポリン1の関係 (2013)
  • Author(s): 三須建郎、藤原一男、高井良樹、西山修平、中島一郎、今野秀彦、糸山泰人、青木正志、Lassmann Hans
  • Organizer: 日本神経学会
  • Place of Presentation: 東京
• [Presentation] アクアポリン4関連アストロサイトパチー病変とアクアポリン1の関係 (2013)
  • Author(s): 三須建郎、藤原一男、高井良樹、西山修平、中島一郎、今野秀彦、糸山泰人、青木正志、Lassmann Hans
  • Organizer: 日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] Diverse mechanisms of tissue injury in neuromyelitis optica (2013)
  • Author(s): T. Misu, R. Höftberger, K. Fujihara, I. Wimmer, Y. Takai, S. Nishiyama, I. Nakashima, H. Konno, M. Bradl, F. Garzuly, Y. Itoyama, M. Aoki, H. Lassmann
  • Organizer: ヨーロッパ多発性硬化症治療研究会（ECTRIMS)
  • Place of Presentation: コペンハーゲン、デンマーク
• [Presentation] MRI findings in optic neuritis of patients with NMO spectrum disorder versus multiple sclerosis (2013)
  • Author(s): K. Kurosawa, T. Misu, S. Nishiyama, D. Sato, H. Kuroda, T. Takahashi, I. Nakashima, K. Fujihara, M. Aoki
  • Organizer: ヨーロッパ多発性硬化症治療研究会（ECTRIMS)
  • Place of Presentation: コペンハーゲン、デンマーク
• [Presentation] A multicentric cross-sectional study of the usefulness of cerebrospinal fluid-glial fibrillary acidic protein (CSF-GFAP) in the diagnosis and prognosis of inflammatory demyelinating diseases (2013)
  • Author(s): S. Nishiyama, T. Misu, Y. Simizu, K. Yokoyama, T. Kageyama, Y. Takai, R. Takano, T. Takahashi, J. Fujimori, S. Sato, I. Nakashima, Y. Itoyama, K. Fujihara, M. Aoki
  • Organizer: ヨーロッパ多発性硬化症治療研究会（ECTRIMS)
  • Place of Presentation: コペンハーゲン、デンマーク
• [Presentation] Aquaporin-4 antibody-seropositive myelitis initially biopsied due to suspected spinal cord tumors: diagnostic considerations (2013)
  • Author(s): Tatsuro Misu, Douglas Kazutoshi Sato, Cristiane Franklin Rocha, Dagoberto Callegaro, Ichiro Nakashima, Masashi Aoki, Kazuo Fujihara, Marco Aurelio Lana-Peixoto
  • Organizer: アジア多発性硬化症治療研究会（PACTRIMS)
  • Place of Presentation: 京都
• [Presentation] A multicentric cross-sectional study of the usefulness of CSF-GFAP in the diagnosis and the prognosis of inflammatory demyelinating diseases. (2013)
  • Author(s): S. Nishiyama, T. Misu, Y. Simizu, K. Yokoyama, T. Kageyama, Y. Takai, R. Takano, T. Takahashi, J. Fujimori, S. Sato, I. Nakashima, Y. Itoyama, K. Fujihara, M. Aoki
  • Organizer: アジア多発性硬化症治療研究会（PACTRIMS)
  • Place of Presentation: 京都
• [Presentation] MRI Findings In Optic Neuritis: Of Patients With Neuromyelitis Optica Spectrum Disorder Versus Multiple Sclerosis (2013)
  • Author(s): K. Kurosawa, T. Misu, S. Nishiyama, D. Sato, H. Kuroda, T. Takahashi, I. Nakashima, K. Fujihara, M. Aoki
  • Organizer: アジア多発性硬化症治療研究会（PACTRIMS)
  • Place of Presentation: 京都
• [Presentation] A Case of Neuromyelitis Optica With Hearing Loss -audiological evidence of therapeutic effect (2013)
  • Author(s): Y Takanashi, T Misu, K Fujihara, T Kawase
  • Organizer: アジア多発性硬化症治療研究会（PACTRIMS)
  • Place of Presentation: 京都
• [Presentation] 腫瘍様炎症性脱髄性疾患におけるアストロサイト破壊性病巣 (2012)
  • Author(s): 高井良樹、三須建郎、他
  • Organizer: 日本神経学会
  • Place of Presentation: 東京
• [Presentation] ヒトアストロサイト一次培養細胞に対する視神経脊髄炎患者IgG・補体の影響 (2012)
  • Author(s): 西山修平、三須建郎、他
  • Organizer: 日本神経学会
  • Place of Presentation: 東京
• [Presentation] NMOにおける非中枢神経系病変 (2012)
  • Author(s): 三須建郎、他
  • Organizer: 日本神経学会
  • Place of Presentation: 東京
• [Presentation] NMO急性期治療としてリツキシマブが有効であった1例 (2012)
  • Author(s): 西山亜由美、西山修平、三須建郎、他
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 軽井沢
• [Presentation] 同心円状脱髄病巣を来したBalo病様中枢性炎症性脱髄性疾患の一生検例 (2012)
  • Author(s): 高井良樹、三須建郎、他
  • Organizer: 神経病理学会
  • Place of Presentation: 新潟
• [Presentation] Pathological features of Aquaporin-4 autoimmunity with cytotoxic edema: the lesson from neuromyelitis optica and related disorders (2012)
  • Author(s): Misu T
  • Organizer: ISBRA WorldCongress
  • Place of Presentation: 札幌
  • Invited
• [Presentation] 視神経脊髄炎アストロサイト病変におけるClasmatodendrosisの意義
  • Author(s): 三須建郎
  • Organizer: 神経病理懇話会
  • Place of Presentation: 三重
• [Presentation] ＮＭＯから見えてきた脱髄疾患の 臨床病理学的特徴
  • Author(s): 三須建郎
  • Organizer: 第１０回 千葉MSフォーラム
  • Place of Presentation: 千葉
  • Invited
• [Presentation] 東北大学におけるAQP４抗体陰性NMOSD
  • Author(s): 三須建郎、佐藤ダグラス、中島一郎、高橋利幸、藤原一男
  • Organizer: 第１１回 MSワークショップ
  • Place of Presentation: 軽井沢
• [Presentation] Pathology of Neuromyelitis Optica
  • Author(s): Misu T
  • Organizer: SENDAI Conference
  • Place of Presentation: 仙台
• [Presentation] 視神経脊髄炎(NMO)の免疫病態～細胞性免疫Up to date～
  • Author(s): 三須建郎
  • Organizer: 神経免疫学会モーニングセミナー
  • Place of Presentation: 軽井沢
  • Invited
• [Book] 多発性硬化症と視神経脊髄炎 (2014)
  • Author(s): 三須 建郎
  • Publisher: 日本臨床社
• [Book] 多発性硬化症(MS)と視神経脊髄炎（NMO)の基礎と臨床 (2012)
  • Author(s): 三須建郎、藤原一男
  • Publisher: 医薬ジャーナル社
• [Book] 最新アプローチ 多発性硬化症と視神経脊髄炎 (2012)
  • Author(s): 三須建郎
  • Publisher: 中山書店
• [Remarks] 東北大学大学院医学系研究科 多発性硬化症治療学
  • URL: http://www.ms.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科 多発性硬化症治療学寄付講座
  • URL: http://www.ms.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科 神経内科
  • URL: http://www.neurol.med.tohoku.ac.jp/