Investigation of interferon signature in NMOSD

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07759
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Osaka University
• Principal Investigator: Tatsusada Okuno 大阪大学, 大学院医学系研究科, 准教授 (00464248)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: NMOSD / IFN シグネーチャー

Outline of Final Research Achievements

Recently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD).We found that enhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed.
Our study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.

Free Research Field

神経免疫学

Academic Significance and Societal Importance of the Research Achievements

NMOSDはアクアポリン４抗体が引き起こす疾患であり、近年多数の生物製剤が使用可能になっているが、どのようにして本来出現しないアクアポリン４抗体が出現に至るのかは不明である。本研究によりNMOSDにおける自然免疫系の関与を明らかにできた。NMOSDの根本的な原因解明につながる成果である。