Elucidating the pathogenesis of demyelinating diseases based on the deletion type copy number variation and the deviated repertoire of gamma delta T cells

• Project/Area Number: 17K16125
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Kyushu University
• Principal Investigator: 篠田 紘司 九州大学, 医学研究院, 助教 (70747998)
• Project Period (FY): 2017-04-01 – 2018-03-31
• Project Status: Discontinued (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: γδ型T細胞 / Vδ2 / Vγ9 / 制御性CD4 T細胞 / 多発性硬化症 / コピー数多型

Outline of Annual Research Achievements

申請者らの研究グループは、2015年にT細胞受容体α鎖及びγ鎖領域に存在するゲノム構造異常が多発性硬化症(MS)疾患感受性を著しく高めることを報告しており、近年MS動物モデルにおける重要な役割が明らかとなってきたγδ型T細胞に着目して本研究を立案した。私たちは、まずヒト末梢血単核細胞をγδ型T細胞、αβ型T細胞、B細胞などの表面抗原、サイトカイン産生を幅広く評価できる実験系を確立した。そして、九州大学病院神経内科でフォローしているMS患者のうち、無治療で寛解期のMS群と健常対象(HC)群でサンプルを収集し、最終的にMS群33名、年齢・性別をマッチさせたHC群22名を対象として分析した。その結果、MS群はHC群と比較してCD4+T細胞中のTreg (CD25+CD127low/-)頻度が低下していた。γδ型T細胞では、MS群はVδ2+、Vδ2+Vγ9+γδ型T細胞、IL-17A+、IFN-γ+、IL-17A+IFN-γ+Vδ2+γδ型T細胞の頻度が低下し、Vδ1+γδ型T細胞の頻度とVδ1/Vδ2比が増加していることを発見した。B細胞サブセットには両群で有意な差はなかった。HC群ではVδ1/Vδ2比がTreg頻度と有意に負相関していたが(r = -0.5927, p = 0.0037)、MS群では関連が消失していた。MS群のVδ1/Vδ2比は障害度スコアExpanded Disability Status Scaleと高度に正相関した(r = 0.5219, p = 0.018)。以上のように、MSにおけるVδ2+Vγ9+γδ型T細胞の著減、Vδ1/Vδ2比とMS身体障害度の強い正相関、健常者で認めるγδ型T細胞とTregとの有意な関連の喪失がMS病態悪化に寄与している可能性を世界で初めて示し、Frontiers in Immunology誌にその成果を報告した。

Research Products

• [Journal Article] Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis (2018)
  • Author(s): Guzailiayi Maimaitijiang†, Koji Shinoda†(†Co-first author), Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Noriko Isobe, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 748-748
  • Peer Reviewed / Open Access
• [Journal Article] Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms in NMOSD (2018)
  • Author(s): Yuri Mizuno, Koji Shinoda, Mitsuru Watanabe, Takuya Matsushita, Ryo Yamasaki, and Jun-ichi Kira.
  • Journal Title: Neurology, Neuroimmunology and Neuroinflammation Volume: 5 Issue: 3
  • DOI: 10.1212/nxi.0000000000000447
  • Peer Reviewed / Open Access
• [Journal Article] HLA genotype and cortical lesions: response to the letter from Spencer et al. (2017)
  • Author(s): Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Ryo Yamasaki, Jun-ichi Kira
  • Journal Title: Multiple Sclerosis Journal Volume: 未決定 Issue: 6 Pages: 819-820
  • DOI: 10.1177/1352458517734072
  • Peer Reviewed
• [Journal Article] A novel mutation in FGD4 causing Charcot-Marie-Tooth disease type 4H with cranial nerve involvement (2017)
  • Author(s): Daisuke Kondo, Koji Shinoda, Ken-ichiro Yamashita, Ryo Yamasaki, Akihiro Hashiguchi, Hiroshi Takashima, Jun-ichi Kira.
  • Journal Title: Neuromuscular Disorders Volume: 27 Issue: 10 Pages: 959-961
  • DOI: 10.1016/j.nmd.2017.07.011
  • Peer Reviewed
• [Journal Article] Re-emergence of a tumefactive demyelinating lesion after initiation of fingolimod therapy (2017)
  • Author(s): Hashimoto Y, Shinoda K, Tanaka E, Uehara T, Matsushita T, Yamasaki R, Kira JI.
  • Journal Title: J Neurol Sci. Volume: 379 Pages: 167-168
  • DOI: 10.1016/j.jns.2017.06.002
  • Peer Reviewed
• [Journal Article] HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis (2017)
  • Author(s): Shinoda Koji、Matsushita Takuya、Nakamura Yuri、Masaki Katsuhisa、Yamasaki Ryo、Yamaguchi Hiroo、Togao Osamu、Hiwatashi Akio、Kira Jun-ichi
  • Journal Title: Multiple Sclerosis Journal Volume: 印刷中 Issue: 6 Pages: 710-720
  • DOI: 10.1177/1352458517707067
  • Peer Reviewed
• [Presentation] 多発脳病変を呈し、脳生検で血管炎の所見を得た抗MOG抗体陽性神経疾患の1例 (2018)
  • Author(s): 馬場 俊知, 渡邉 充, 篠田 紘司, 貞島 祥子, 松瀬 大, 金子 仁彦, 高橋 利幸, 岩城 徹, 吉良 潤一
  • Organizer: 第221回日本神経学会九州地方会
• [Presentation] Branchial myorhythmiaを来したneuropsychiatric SLEの一例 (2018)
  • Author(s): 宇根 隼人, 江 千里, 篠田 紘司, 渡邉 充, 上原 平, 松瀬 大, 山﨑 亮, 飛松 省三, 柴崎 浩, 吉良 潤一
  • Organizer: 第221回日本神経学会九州地方会
• [Presentation] 多発性硬化症大脳皮質病巣と高次脳機能障害の密接な関係およびHLAクラスII遺伝子アリルとの相関 (2018)
  • Author(s): 篠田 紘司, 中村 優理, 渡邉 充, 磯部 紀子, 松下 拓也, 山﨑 亮, 吉良 潤一
  • Organizer: 厚生労働省難治性疾患(神経免疫疾患)政策および実用化研究班平成29年度合同班会議
• [Presentation] 水痘帯状疱疹ウイルス（VZV）関連脳血管炎及び脊髄炎が急速に進行し剖検にて脊髄にVZVを確認し得た一例 (2017)
  • Author(s): 前田 泰宏, 野上 健一郎, 前田 教寿, 緒方 英紀, 渡邉 充, 篠田 紘司, 山﨑 亮, 岩城 徹, 吉良 潤一.
  • Organizer: 第220回日本神経学会九州地方会
• [Presentation] A distinct repertoire of the γδ T cell population is associated with disease severity of multiple sclerosis (2017)
  • Author(s): Koji Shinoda, Guzailiayi Maimaitijiang, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Contribution of Cortical Lesions to Cognitive Dysfunction in Japanese Patients with Multiple Sclerosis (2017)
  • Author(s): Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Shiori Sakai, Haruka Nomiyama, Ryo Yamasaki, Osamu Togao, Akio Hiwatashi and Jun-ichi Kira
  • Organizer: The 10th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)
  • Int'l Joint Research
• [Presentation] Deviated Repertoire of γδ T Cells is Associated with Disease Severity of Multiple Sclerosis (2017)
  • Author(s): Guzailiayi Maimaitijiang, Koji Shinoda, Yuri Nakamura, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Organizer: The 10th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)
  • Int'l Joint Research
• [Presentation] Differential Associations of Spinal Cord Atrophy with Clinical Disability between Japanese Patients with Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder (2017)
  • Author(s): Yuri Nakamura, Liu Zhiwen, Koji Shinoda, Takuya Matsushita, Akio Hiwatashi, Jun-ichi Kira
  • Organizer: The 10th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)
  • Int'l Joint Research
• [Presentation] A distinct repertoire of the γδ T cell population is associated with disease severity of multiple sclerosis (2017)
  • Author(s): Koji Shinoda, Guzailiayi Maimaitijiang, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Organizer: MSParis2017
  • Int'l Joint Research
• [Presentation] Distinct associations of cross-sectional spinal cord areas with clinical disability in Japanese patients with multiple sclerosis and neuromyelitis optica spectrum disorder with aquaporin-4-IgG (2017)
  • Author(s): Yuri Nakamura, Liu Zhiwen, Koji Shinoda, Takuya Matsushita, Akio Hiwatashi, Jun-ichi Kira
  • Organizer: MSParis2017
  • Int'l Joint Research
• [Presentation] HLA-DRB1*04:05 is associated with Intracortical Lesions on 3-Dimensional Double Inversion Recovery Imaging in Japanese Patients with Multiple Sclerosis (2017)
  • Author(s): Koji Shinoda, Takuya Matsushita, Yuri Nakamura, Katsuhisa Masaki, Ryo Yamasaki, Osamu Togao, Akio Hiwatashi and Jun-ichi Kira
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Derangement of γδ T cell subsets is associated with disease severity of multiple sclerosis. (2017)
  • Author(s): Guzailiayi Maimaitijiang, Koji Shinoda, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Associations between spinal cord atrophy and disease severity in Japanese patients with multiple sclerosis and neuromyelitis optica spectrum disorders (2017)
  • Author(s): Zhou Liu, Yuri Nakamura, Koji Shinoda, Takuya Matsushita, Akio Hiwatashi, Jun-ichi Kira
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] γδ型T細胞受容体のレパトワ偏倚は多発性硬化症の臨床的障害度と有意に関連する (2017)
  • Author(s): 篠田 紘司, グザリアイ ママティジャン, 中村 優理, 眞﨑 勝久, 松下 拓也, 山﨑 亮, 吉開 泰信, 吉良 潤一
  • Organizer: 第29回日本神経免疫学会学術集会
• [Presentation] 多発性硬化症患者におけるT細胞受容体レパトアの解析 (2017)
  • Author(s): 林 史恵, 磯部 紀子，グザリアイ ママティジャン, 中村 優理, 篠田 紘司, 松下 拓也, 吉良 潤一
  • Organizer: 第29回日本神経免疫学会学術集会
• [Presentation] オリゴデンドログリアのコネキシン47欠失は慢性進行型実験的自己免疫性脳脊髄炎を悪化させる (2017)
  • Author(s): 趙 奕楠, 山口 浩雄, 宇根 隼人, 飯沼 今日子, 眞﨑 勝久, 篠田 紘司, 吉良 潤一
  • Organizer: 第29回日本神経免疫学会学術集会
• [Presentation] Clinical and genetic features of Japanese patients with multiple sclerosis based on Japan multiple sclerosis biobank (2017)
  • Author(s): 松下拓也, 中村優理, 新野正明, 深浦彦彰, 田中正美, 越智博文, 神田隆, 横田隆徳, 松井真, 楠進, 寺山靖夫, 河内泉, 大橋高志, 下濱俊, 西山和利, 中辻裕司, 越智一秀, 錫村明生, 山本健, 山﨑亮, 河野祐治, 辻省次, 夛田まや子, 樋野村亜希子, 松山晃文, 清水優子, 永石彰子, 岡田和将, 篠田紘司, 磯部紀子, 吉良潤一
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Derangement of γδ T cell repertoire is associated with disease severity of multiple sclerosis (2017)
  • Author(s): Koji Shinoda, Guzailiayi Maimaitijiang, Yuri Nakamura, Katsuhisa Masaki, Takuya Matsushita, Ryo Yamasaki, Yasunobu Yoshikai, Jun-ichi Kira
  • Organizer: MS Summer College 2017
• [Presentation] 全身性強皮症に多発単神経炎を合併し、MR neurographyで末梢神経腫大を認めた一例 (2017)
  • Author(s): 山元 伸昭, 山口 高弘, 篠田 紘司, 渡邉充, 山﨑 亮, 吉良 潤一
  • Organizer: 第218回日本神経学会九州地方会
• [Presentation] MR neurographyで多発性の末梢神経腫大・神経根腫大を認めた抗AQP4抗体陽性視神経脊髄炎の一例 (2017)
  • Author(s): 水野 裕理, 篠田 紘司, 渡邉 充, 馬場 俊和, 田中 公裕, 山﨑 亮, 吉良 潤一
  • Organizer: 第218回日本神経学会九州地方会
• [Presentation] 日本人多発性硬化症における皮質病巣数はHLA-DRB1*04:05により規定される (2017)
  • Author(s): 篠田 紘司, 松下 拓也, 中村 優理, 眞﨑 勝久, 栂尾 理, 樋渡 昭雄, 吉良 潤一
  • Organizer: 第114回日本内科学会学術集会