多発性硬化症におけるB細胞免疫に関する研究

• Project/Area Number: 21591068
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Hokkaido University
• Principal Investigator: 新野 正明 Hokkaido University, 医学(系)研究科(研究院), その他 (00443961)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脳・神経 / 免疫学 / 多発性硬化症 / 遺伝子 / B細胞 / Toll-like receptor

Research Abstract

【背景】近年のMS有病率上昇の一因に衛生仮説が提唱され、その背景に自然免疫の関与が示唆されている。Toll-like receptor (TLR)は自然免疫での病原体認識分子であるが、自然免疫のみならず獲得免疫をも誘導する。TLR9はB細胞と形質細胞様樹状細胞に発現し、CpGDNAがリガンドに同定されている。一方、近年B細胞産生性IL-10による免疫調節性機能が注目され、MSでの低下が報告されている。MSにおけるTLR9を介した免疫調節性機能の可能性について検討することを目的とした。【方法】MS36例(再発期6例、寛解期30例)、健常者10例を対象とし、寛解期MS群は未治療10例、インターフェロン(IFN)β-1a治療10例、IFNβ-1b治療10例とした。対象者の末梢血を採取し、Flow cytometryでCD19陽性B細胞表面CD27、CD80、CD86とB細胞内TLR9の発現を測定した。またB細胞を分離し、0.25μMのCpGDNA(ODN2006)で24時間刺激したのち、ELISAで上清中のIL-10、IL-12(p40)、TNF-α、Lymphotoxin-αを測定した。【結果】CpGDNA刺激によるB細胞のIL-10産生はMS全体で有意に低く、IL-12(p40)産生は再発期MSで有意に高かった。memory B細胞におけるTLR9のMean Fluorescence IntensityはMSで有意に低く、またB細胞のIL-10産生と有意な正の相関を呈した。【結論】MSではTLR9を介したB細胞のIL-10産生が低下しており、これはmemory B細胞のTLR9発現低下に起因している可能性があることが判明した。

Research Products

• [Journal Article] Vitamin D metabolites and multiple sclerosis (2011)
  • Author(s): Niino M
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 82 Pages: 121-121
  • Peer Reviewed
• [Journal Article] Vitamin D and its immunoregulatory role in multiple sclerosis (2010)
  • Author(s): Niino M
  • Journal Title: Drugs Today Volume: 46 Pages: 95-100
  • Peer Reviewed
• [Journal Article] The role of B cells in multiple sclerosis : Implications for B-cell-targeted thrapy (2010)
  • Author(s): Hirotani M, et al.
  • Journal Title: Curr Med Chem Volume: 17 Pages: 3215-3222
  • Peer Reviewed
• [Journal Article] Impact and characteristics of quality of life in Japanese patients with multiple sclerosis (2010)
  • Author(s): Kikuchi H, et al.
  • Journal Title: Qual Life Res Volume: 20 Pages: 119-131
  • Peer Reviewed
• [Journal Article] Pharmacogenomics of multiple sclerosis : Current status and potential applications (2010)
  • Author(s): Niino M, et al.
  • Journal Title: Curr Pharmacogenomics Person Med Volume: 8 Pages: 273-279
  • Peer Reviewed
• [Journal Article] Five-year follow-up with low-dose tacrolimus in myasthenia gravis (2010)
  • Author(s): Minami N, et al
  • Journal Title: J Neurol Sci Volume: 300 Pages: 59-62
  • Peer Reviewed
• [Journal Article] Is vitamin D relevant in reducing risk of multiple sclerosis? (2010)
  • Author(s): Niino M
  • Journal Title: Clinical Laboratory International Volume: 34 Pages: 20-22
• [Journal Article] An update on the treatment options for multiple sclerosis (2010)
  • Author(s): Niino M
  • Journal Title: Expert Rev Clin Immunol 6 Pages: 77-88
  • NAID: 40019510560
  • Peer Reviewed
• [Journal Article] Memory and naive B-cell subsets in patients with multiple sclerosis (2009)
  • Author(s): Niino M
  • Journal Title: Neurosci Lett 464 Pages: 74-78
  • Peer Reviewed
• [Journal Article] Estrogens as potential therapeutic agents in multiple sclerosis (2009)
  • Author(s): Niino M
  • Journal Title: Cent Nerv Syst Agents Med Chem 9 Pages: 87-94
  • Peer Reviewed
• [Journal Article] Relationship between Barkhof criteria and clinical features of multiple sclerosis in northern Japan (2009)
  • Author(s): Nakamura M
  • Journal Title: Mult Scler 15 Pages: 1450-1458
  • Peer Reviewed
• [Journal Article] Decreased IL-10 production mediated by Toll-like receptor 9 in B cells in multiple sclerosis
  • Author(s): Hirotani M
  • Journal Title: J Neuroimmunol (In press)
  • Peer Reviewed
• [Presentation] Decreased interferon-alpha production in response to CpG DNA dysre gulates cytokine responses in patients with multiple sclerosis (2010)
  • Author(s): Hirotani M, et al.
  • Organizer: 26^<th> Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: Gothenburg, Sweden
  • Year and Date: 2010-10-15
• [Presentation] 多発性硬化症におけるB細胞subsetの検討 (2010)
  • Author(s): Niino M, et al.
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Year and Date: 2010-05-22
• [Presentation] 多発性硬化症の形質細胞様樹状細胞によるCpG-A反応性インターフェロンα産生の低下 (2010)
  • Author(s): Hirotani M, et al.
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Year and Date: 2010-05-21
• [Presentation] Changes in memory and naive B-cell subsets according to therapy and disease status in MS patients (2009)
  • Author(s): Niino M
  • Organizer: 25^<th> Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: Dusseldorf, Germany
  • Year and Date: 2009-09-10
• [Presentation] Immunoregulatory function mediated by Toll-like receptor 9 in B cells in multiple sclerosis (2009)
  • Author(s): Hirotani M
  • Organizer: 25^<th> Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: Dusseldorf, Germany
  • Year and Date: 2009-09-10
• [Presentation] Relationship Between Barkhof criteria and clinical features of multiple sclerosis in northern Japan (2009)
  • Author(s): Nakamura M
  • Organizer: 25^<th> Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: Dusseldorf, Germany
  • Year and Date: 2009-09-10
• [Presentation] IFNβ投与群MS患者におけるB細胞表面抗原の比較検討 (2009)
  • Author(s): 新野正明
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台市国際センター
  • Year and Date: 2009-05-22