Elucidation of autoimmune mechanisms and developement of novel therapy for demyelinating diseases based on genetic and envrionmental risk factors and disease-specific anti-neural antibodies

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19H01045
• Research Institution: International University of Health and Welfare
• Principal Investigator: 吉良 潤一 国際医療福祉大学, 福岡薬学部, 教授 (40183305)
• Co-Investigator(Kenkyū-buntansha): 松下 拓也 九州大学, 大学病院, 講師 (00533001) ; 山崎 亮 九州大学, 医学研究院, 准教授 (10467946) ; 藤井 敬之 九州大学, 大学病院, 医員 (30822481) ; 緒方 英紀 九州大学, 大学病院, 助教 (90778838)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 多発性硬化症 / 慢性炎症性脱髄性多発神経炎 / アトピー性脊髄炎 / 自己抗体 / ノド抗体 / 神経障害性疼痛

Outline of Annual Research Achievements

慢性脱髄疾患は、中枢神経(CNS)を侵す多発性硬化症(MS)と末梢神経を侵す慢性炎症性脱髄性多発神経炎(CIDP)が代表で、両者の合併である中枢末梢連合脱髄症(CCPD)や、視神経脊髄炎(NMO)、アトピー性脊髄炎などがある。これらは自己免疫機序が示唆されているが、自己抗原が確立していないものが多い。そこで本研究では、自己抗体未発見のMSとCIDPを主たる対象として、特徴的な病像を呈するサブグループを特定できる自己抗体バイオマーカーを探索・同定すること、及び同定された病態特異的な自己抗体・自己反応性T細胞の作用を再現した病態モデルを作成することを主な目的としている。CIDPの新規自己抗原の探索として、坐骨神経と後根神経節標本を用いた組織免疫染色によりランビエ絞輪部と後根神経節のsatellite gliaを特徴的に染色する5例の陽性例を見出した。、その責任抗原として、genetic strategyにより、leucine-rich repeat LGI family, member 4 (LGI4)を同定した。また新たな自己抗体の探索のために、マウス視神経を用いた組織免疫染色法を開発している。マウスモデルの作成においては、抗Plexin D1抗体陽性アトピー性脊髄炎患者由来IgGのマウス髄腔内に投与により神経障害性疼痛を再現し、脊髄後根神経節の小型痛覚ニューロンの特異的な活性化を証できた。さらに、マウス坐骨神経と視神経に患者血清より精製抽出したIgGの注入による受け身移入実験を進めている。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

マウスモデルの作成と新規自己抗体の探索と責任抗原の同定が遅れたため。

Strategy for Future Research Activity

新規自己抗原の探索と、その責任抗原の同定を進める。マウス坐骨神経と視神経への患者IgGの注入による受動免疫モデルを完成させる。

Research Products

• [Journal Article] Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis. (2020)
  • Author(s): Fujii T, Yamasaki R, Miyachi Y, Nagata S, Maimaitijiang G, Nakamura Y, Shinoda K, Matsushita T, Isobe N, Kira J
  • Journal Title: J Neurol Sci Volume: 409 Pages: 116619
  • DOI: 10.1016/j.jns.2019.116619
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis. (2020)
  • Author(s): Zhao Y, Yamasaki R, Yamaguchi H, Nagata S, Une H, Cui Y, Masaki K, Nakamuta Y, Iinuma K, Watanabe M, Matsushita T, Isobe N, Kira J
  • Journal Title: Proc Natl Acad Sci USA Volume: 117 (4) Pages: 2160-2169
  • DOI: 10.1073/pnas.1901294117
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy. (2020)
  • Author(s): Ogata H, Isobe N, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Kira J
  • Journal Title: J Neuroimmunol Volume: 339 Pages: 577139
  • DOI: 10.1016/j.jneuroim.2019.577139
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis. (2020)
  • Author(s): Shinoda K, Matsushita T, Nakamura Y, Masaki K, Sakai S, Nomiyama H, Togao O, Hiwatashi A, Niino M, Isobe N, Kira J
  • Journal Title: Scientific Reports Volume: 10(1) Pages: 52228
  • DOI: 10.1038/s41598-020-61012-3.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk HLA-DRB1 alleles differentially influence brain and lesion volumes in Japanese patients with multiple sclerosis. (2020)
  • Author(s): Fukumoto S, Nakamura Y, Watanabe M, Isobe N, Matsushita T, Sakoda A, Hiwatashi A, Shinoda K, Yamasaki R, Tsujino A, Kira J
  • Journal Title: J Neurol Sci Volume: 413 Pages: 116768
  • DOI: 10.1016/j.jns.2020.116768
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod. (2020)
  • Author(s): Watanabe M, Nakamura Y, Isobe N, Tanaka M, Sakoda A, Hayashi F, Kawano Y, Yamasaki R, Matsushita T, Kira J
  • Journal Title: J Neuroinflammation Volume: 17(1) Pages: 206
  • DOI: 10.1186/s12974-020-01865-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Painful trigeminal neuropathy associated with anti-Plexin D1 antibody (2020)
  • Author(s): Fujii T, Yamasaki R, Miyachi Y, Iinuma K, Hashimoto Y, Isobe N, Matsushita T, Kira J
  • Journal Title: Neurology: Neuroimmunology & Neuroinflammation Volume: 7 Pages: e819
  • DOI: 10.1212/NXI.0000000000000819
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic factors for susceptibility to and manifestations of neuromyelitis optica. (2020)
  • Author(s): Matsushita T, Masaki K, Isobe N, Sato S, Yamamoto K, Nakamura Y, Watanabe M, Suenaga T, Kira J
  • Journal Title: Ann Clin Transl Neurol Volume: 7 Pages: 2082-2093
  • DOI: 10.1002/acn3.51147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Balo’s disease and neuromyelitis optica spectrum disorders. (2020)
  • Author(s): Hayashida S, Masaki K, Suzuki SO, Yamasaki R, Watanabe M, Koyama S, Isobe N, Matsushita T, Takahashi K, Tabira T, Iwaki T, Kira J
  • Journal Title: Brain Pathol Volume: 30(6) Pages: 1144-1157
  • DOI: 10.1111/bpa.12898
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Continued increase of multiple sclerosis and neuromyelitis optica in Japan. Updates from the 5th Nationwide survey (2020)
  • Author(s): Kira J, Isobe N, Niino M, et al.
  • Organizer: 145th Annual Meeting of the American Neurological Association 2020
  • Int'l Joint Research
• [Presentation] Two subtypes of anti-neurofascin 155/contactin-1 antibody-negative CIDP by CSF cytokine profiling (2020)
  • Author(s): Zhang X, Ogata H, Yamasaki R, Kaida K, Kuwahara M, Kusunoki S, Matsushita T, Isobe N, Kira J
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Frequent subclinical cranial nerve involvement in anti-neurofascin 155 antibody-positive CIDP (2020)
  • Author(s): Ogata H, Zhang X, Inamizu S, Yamasaki R, Matsushita T, Isobe N, Kira J
  • Organizer: 2020 Peripheral Nerve Society Annual Meeting
  • Invited
• [Presentation] Serum glial fibrillary acidic protein, but not S100B or neurofilament light chain predicts future relapses in neuromyelitis optica spectrum disorders. (2020)
  • Author(s): Watanabe M, Isobe N, Matsushita T, Maceski AM, Nakamura Y, Masaki K, Kira J, Leppert D, Kuhle J
  • Organizer: MSVirtual2020 (8th Joint ACTRIMS-ECTRIMS Meeting)
  • Invited