Elucidation of the pathogenesis of immune disorders in MIRAGE syndrome and its application to the development of new therapies

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16942
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: National Defense Medical College
• Principal Investigator: Sekinaka Yujin 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 小児科学, 助教 (90837238)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: MIRAGE症候群 / SAMD9 / 原発性免疫不全症 / 自己炎症症候群 / 樹状細胞

Outline of Final Research Achievements

The purpose of this study was to elucidate the pathogenesis of immunodeficiency and autoinflammation in MIRAGE syndrome caused by hyperfunctional mutations of SAMD9, to develop new treatment methods, and to clarify the function of SAMD9 in the immune system.
(1) Patients with MIRAGE syndrome show abnormalities in immune cells such as dendritic cells, which are involved in immunodeficiency symptoms and autoinflammatory disease-like conditions.(2) The immune abnormalities in MIRAGE syndrome patients may progress over time and require long-term follow-up.(3) Analysis using diseased iPS cells suggests that dendritic cells in MIRAGE syndrome exhibit maturation defects and abnormal cell morphology, which may be the cause of the immune abnormalities. Further clarification of the pathogenesis of MIRAGE syndrome will be sought through analysis of cellular functions.

Free Research Field

Pediatrics

Academic Significance and Societal Importance of the Research Achievements

本研究では、MIRAGE症候群の免疫異常に焦点を絞り、免疫不全および自己炎症の発症機序を解明し新規治療法を開発する事、原因遺伝子SAMD9の免疫系における機能を明らかにする事を目的とした。これまでMIRAGE症候群の詳細な免疫学的解析は行われておらず、本研究で免疫学的な異常を同定することで、患者の感染症及び自己炎症症状の予防及び治療に活かすことが出来た。また、SAMD9の機能を解析することで、免疫系におけるSAMD9の役割を知ることが出来た。近年、免疫不全と自己炎症を合併する免疫異常が注目を浴びているが、本研究により樹状細胞の分化異常、機能異常からその病態を解明し、新たな疾患概念を構築した。