Elucidation of pathogenesis of autoimmune-mediated interstitial lung disease based on epigenomic analysis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03697
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokyo
• Principal Investigator: OKAMURA Tomohisa 東京大学, 医学部附属病院, 特任准教授 (10528996)
• Co-Investigator(Kenkyū-buntansha): 駒井 俊彦 東京大学, 医学部附属病院, 助教 (50803938) ; 藤尾 圭志 東京大学, 医学部附属病院, 教授 (70401114) ; 住友 秀次 東京大学, 医学部附属病院, 講師 (20392996)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 間質性肺炎 / 自己免疫性疾患 / T細胞 / TGF-β1

Outline of Final Research Achievements

The aim of this study is to elucidate the mechanisms of progressive fibrosis in connective tissue disease (CTD) -associated interstitial lung diseases (ILD). First, we confirmed the synergistic effects of cytokines including TGF-β1 on fibroblast activation. Second, we identified a novel effector memory CD4+ T cell subset that highly expresses TGFB1 in the bronchoalveolar lavage fluid in ILD. ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) revealed the epigenetic mechanisms that regulate the expression of TGFB1 on the CD4+ T cell subset. These findings indicate that the pro-fibrotic CD4+ T cell subset might play a pivotal role in the progression of lung fibrosis via TGFB1 production. Further detailed analysis of the pro-fibrotic CD4+ T cell induction mechanisms will provide a novel therapeutic target for CTD-associated ILD.

Free Research Field

免疫学、機能ゲノム学、膠原病

Academic Significance and Societal Importance of the Research Achievements

間質性肺炎は、肺胞以外の肺を支える間質部分を中心とした炎症および激しい線維化を来す疾患であり、代表的自己免疫疾患であるリウマチ・膠原病疾患の予後を規定する。本課題では、自己免疫性疾患患者の間質性肺炎の肺胞洗浄液より、線維化促進性のサイトカインを高発現する新規T細胞を同定し、その線維化促進メカニズムを明らかとした。本解析結果は、間質性肺炎治療の新規創薬ターゲット同定に繋がる可能性を内包している。