Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model

2024 Fiscal Year Final Research Report

• Project/Area Number: 23K14783
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: International University of Health and Welfare
• Principal Investigator: Zhang Xu 国際医療福祉大学, トランスレーショナルニューロサイエンスリサーチセンター, 特任助教 (60892669)
• Project Period (FY): 2023-04-01 – 2025-03-31
• Keywords: 多発性硬化症 / 脱髄疾患 / 視神経脊髄炎 / ランビエ絞輪 / 自己抗体 / ノドパチー / アストログリア / オリゴデンドログリア

Outline of Final Research Achievements

In multiple sclerosis (MS), widespread nodal protein loss is observed beyond the areas of demyelination. In this study, we discovered a novel nodal antibody to ATPase Na+/K+ transporting subunit alpha 2/3 (ATP1A2/3) in idiopathic central nervous system inflammatory demyelinating disease (IDD). We developed a live cell-based assay for anti-ATP1A2/3 antibody. We found that anti-ATP1A2/3antibody-positive IDD showed higher frequency of juvenile onset, higher EDSS scores, greater relapse numbers, higher frequency of optic nerve involvement, and higher frequency of long spinal cord lesions than anti-ATP1A2/3 antibody negative MS. Serum glial fibrillary acidic protein levels measured by single molecule array were increased at relapse and progressive phases in anti-ATP1A2/3 antibody-positive IDD, and related to disability. In conclusion, anti-ATP1A2/3 antibody-positive IDD shows greater disability and larger lesions than anti-ATP1A2/3 antibody-negative MS through astroglia damage.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究で初めて中枢神経ノド抗体を発見でき、多発性硬化症で初期からみられる原因不明のノドパチーには自己抗体介在性機序が関わっていることを示すことができた。特に進行型多発性硬化症で、新規発見した抗ATP1A2/3抗体の陽性率が高く、抗体陽性例は重症化しやすいことから、抗体介在性機序が病態の進行に重要であることがわかった。一方、既知抗体が陰性の多発性硬化症以外の脱髄疾患は原因が全く不明であった。そのうち、既知抗体陰性の視神経脊髄炎や中枢末梢連合脱髄症で抗ATP1A2/3抗体が高率陽性になることから、これらの疾患の発症に抗ATP1A2/3抗体が関わっていることを初めて示すことができた。