Elucidation of pathogenesis and identification of novel causative gene of primary immunodeficiency due to PIP3-related molecular abnormality.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04233
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Defense Medical College
• Principal Investigator: Nonoyama Shigeaki 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, 教授 (40280961)
• Co-Investigator(Kenkyū-buntansha): 今井 耕輔 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (90332626)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 小児免疫 / アレルギー / 膠原病学

Outline of Final Research Achievements

We developed a rapid diagnostic method for Activated Pi3Kδ syndrome (APDS), a primary immunodeficiency disease. Using this method, large numbers of APDS patients were diagnosed and analysed. We found the presence of cellular immunodeficiency in APDS patients. A novel causative gene, PTEN, was identified. The results of hematopoietic stem cell transplantation were summarized. Post-transplant engraftments were evaluated by analyzing the PI3K mutation using digital PCR.
Increased phosphorylation of FOXO1 was found in T cells of APDS patients. After phosphorylation by PI3K activation signal, FOXO1 translocates to extra-nucleus, and the transcriptional activity is suppressed. It was considered that immunodeficiency is caused by the decreased expression of immune-related genes transcribed by FOXO1. ERK phosphorylation was found to be enhanced in APDS patient B cells. The increased phosphorylation of ERK was considered to be the cause of lymphadenopathy in APDS.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

原発性免疫不全症であるActivated Pi3Kδsyndrome(APDS)の新規遺伝子を同定した。迅速診断法を開発した。多数患者を解析し細胞性免疫不全があることを見出した。造血幹細胞移植の成績をまとめた。細胞内シグナル異常を解析しAPDSの大きな問題である免疫不全およびリンパ節腫脹の原因を解明した。難病であるAPDSの診断法、病態解明および適切な治療法の確立に貢献した。