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2007 Fiscal Year Final Research Report Summary

Analysis of pathogenic roles of MuSK antibodies in myasthenia gravis using the experimental animal models.

Research Project

Project/Area Number 18590946
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionTokyo Metropolitan Institute of Gerontology (2007)
Ehime University (2006)

Principal Investigator

SHIGEMOTO Kazuhiro  Tokyo Metropolitan Institute of Gerontology, Tokyo Metropolitan Institute of Gerontology, Research Team for Molecular Biomarkers, Team Leader (40284400)

Co-Investigator(Kenkyū-buntansha) UEDA Norifumi  Tokyo Metropolitan Foundation for Research on aging Promotion Human Welfare, Dept. of Molecular Pathology, Professor (30030886)
MATSUDA Seiji  Tokyo Metropolitan Foundation for Research on aging Promotion Human Welfare, Dept. of Anatomy and Embryology, 教授 (40173843)
Project Period (FY) 2006 – 2007
KeywordsMuSK / Myasthenia gravis / Neuromuscular junction
Research Abstract

We have provided the evidence that active immunization with MuSK protein reproduces myasthenia gravis in animals. Next we focus on how MuSK antibodies cause MG. The pathogenic roles of MuSK antibodies in MG have been questioned as the number of AChRs is not reduced and complement is not deposited at the NMJ of biceps brachii muscles MuSK-positive patients with MG. The mechanisms of MG caused by AChR antibodies are well delineated, but the revealed mechanisms are not able to simply apply to MG with MuSK antibodies. MuSK antibodies have been identified as predominantly IgG4 subclass, which does not activate complement. We found that agrin-induced clustering of AChR was strongly blocked in the presence of MuSK antibodies, whereas absorption of the antibodies with purified MuSK products prevented this blocking effect. These results showed that the MuSK antibodies effectively inhibited the formation of agrin-induced AChR clustering. Intriguingly, the monovalent Fab fragments of MuSK antibodies from rabbits with EAMG also inhibited AChR clustering by agrin on C2C12 cells, indicating that complement-mediated mechanisms are not necessarily required for such inhibition. We then examined the reduced expression of AChR at NMJ in soleus muscles of paretic and normal rabbits by fluorescence microscopy. In addition, the structure of NMJ in our paretic rabbits, as well as the size and branching of the motor terminals, were significantly reduced. Electron microscopic observations of NMJ in rabbits with EAMG induced by injection of MuSK protein demonstrated a significant loss of complexity of convoluted synaptic folds but no destruction, and EAMG model cited here resembles the phenotype of humans with MG and MuSK antibodies. Our results showed that MuSK antibodies inhibit both anterograde and retrograde signals required for maintaining the synaptic structures in mature NMJ.

  • Research Products

    (14 results)

All 2008 2007 2006

All Journal Article (9 results) (of which Peer Reviewed: 6 results) Presentation (5 results)

  • [Journal Article] Experimentally induced myasthenia gravis with muscle-specific kinase.2008

    • Author(s)
      Shigemoto K. Kubo, S.(他13名)
    • Journal Title

      Ann. N.Y. Acad. Sci. 2008. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Myastenia gravis induced by autoantibodies against MuSK2008

    • Author(s)
      Shigemoto K
    • Journal Title

      Acta Myologica. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Anti-Alkakline Phosphatase Antibody positive Myasthenia Gravis.2007

    • Author(s)
      Konishi, T. Ohta, K. Shigemoto, K. Ohta, M.
    • Journal Title

      J Neurol Scineces. 263

      Pages: 89-93

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Clinical and experimental features of MuSK antibody positive MG in Japan.2007

    • Author(s)
      Ohta, M. Shigemoto, K.(他4名)
    • Journal Title

      Eur J Neurology 14

      Pages: 1029-1034

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] 特集免疫性神経・筋疾患の動物モデル.2007

    • Author(s)
      重本和宏
    • Journal Title

      アニテックス 19-6

      Pages: 17-23

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] 神経接合部疾患における抗MuSK抗体と病態機序2007

    • Author(s)
      丸山直記、重本和宏
    • Journal Title

      臨床神経学 47

      Pages: 842-844

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Clinical and experimental features of MuSK antibody positive MG in Japan.2007

    • Author(s)
      Ohta K, Shigemoto K, Fujinami A, Maruyama N, Konishi T, Shimoda Y, & Ohta M.
    • Journal Title

      Eur J Neurol 14(9)

      Pages: 1029-1034

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Anti-alkaline phosphatase antibody positive myasthenia gravis.2007

    • Author(s)
      Konishi T, Ohta K, Shigemoto K & Ohta M.
    • Journal Title

      J Neurol Sci 263(1-2)

      Pages: 89-93

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Induction of myasthenia by immunization against muscle-specific kinase.2006

    • Author(s)
      Shigemoto K, Kubo S, Maruyama N, Hato N., Yamada T, Jie C, Kobayashi N, Mominoki K, Abe Y, Ueda N, & Matsuda S.
    • Journal Title

      J Clin Invest 116(4)

      Pages: 1016-1024

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Myasthenia gravis induced by autoantibodies against MuSK.2007

    • Author(s)
      Shigemoto, K.
    • Organizer
      7^<th> Japanese-French Workshop on Development of Molecular Therpy toward Muscular Dystrophy
    • Place of Presentation
      神奈川県湘南国際村
    • Year and Date
      20070608-09
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] ・神経接合部疾患における抗MuSK抗体と病態機序2007

    • Author(s)
      丸山直記、重本和宏
    • Organizer
      第48回日本神経学会総会(シンポジュウム).
    • Place of Presentation
      名古屋
    • Year and Date
      20070516-18
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Experimentally induced myasthenia gravis with muscle-specific kinase.2007

    • Author(s)
      Shigemoto K.
    • Organizer
      N.Y.Acad.Symposium, 11th International Conference on Myasthenia Gravis and related disorders.
    • Place of Presentation
      Chicago USA
    • Year and Date
      20070000
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Myasthenia gravis induced by autoantibodies against MusK.2007

    • Author(s)
      Shigemoto K.
    • Organizer
      7th Japanese-French Workshop on "Development of Molecular Therapy toward Muscular Dystrophy"
    • Place of Presentation
      kanagawa, Japan.
    • Year and Date
      20070000
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Experimentally induced myasthenia gravis with muscle-specific kinase.2007

    • Author(s)
      Shigemoto, K.
    • Organizer
      N.Y. Acad. Symposium, 11^<th> International Conference on Myasthenia Gravis and related disorders.
    • Place of Presentation
      Chicago USA
    • Year and Date
      2007-05-13
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2010-02-04  

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