Discovery of novel anti-LGI4 antibodies in chronic demyelinating polyneuropathy and elucidation of its mechanism

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15703
• 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センター, 特任助教 (60892669)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 脱髄疾患 / 慢性炎症性脱髄性多発神経炎 / ランビエ絞輪 / ノド抗体 / LGI4 / 後根神経節 / satellite glia / IgG4

Outline of Final Research Achievements

Sera from 6 CIDP patients selectively bound to the nodal regions of sciatic nerves and dorsal root ganglion (DRG) satellite glia. IgG from all patients stained a 60 kDa band on western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine rich repeat LGI family member 4 (LGI4) to be a candidate antigen. A commercial anti-LGI4 antibody and IgG from all seropositive CIDP patients showed the same immunostaining patterns on DRG and cultured rat Schwann cells, and bound to LGI4-overexpression lysates by western blotting. In cultured rat Schwann cells constitutively expressing LGI4, LGI4 siRNA effectively down-regulated LGI4 and reduced patients'IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing a disintegrin and metalloprotease domain-containing protein 22 (ADAM22), an LGI4 receptor, significantly reduced expression of Krox20, but not Periaxin.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

慢性炎症性脱髄性多発神経炎(CIDP)は、抗原は未解明で根治療法はない。一部のCIDPでは、ランビエ絞輪部に局在するneurofascin 155などのノド蛋白に対するIgG4クラスの自己抗体が報告され、特異な病像を呈することから自己免疫性ノドパチーという新しい疾患概念が生まれた。しかし、類似の特徴を示すが、ノド抗体陰性例も少なくない。本研究で新たなノド抗原として、leucine-rich repeat LGI family, member 4 (LGI4)を同定できた。この新たなノドパチーの発見は、抗原未同定のCIDP患者の診断と治療の導入における意義が極めて大きい。