Pathological characterization of inflammatory bowel disease based on primary immunodeficiency

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Shinobu Tamura 和歌山県立医科大学, 医学部, 准教授 (10364085)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 原発性免疫不全症 / 炎症性腸疾患 / DNAリガーゼⅣ / 遺伝子再構成障害 / LIG4症候群 / Th1細胞 / 非相同末端結合

Outline of Final Research Achievements

Non-homologous end joining (NHEJ) is critical for V(D)J recombination in lymphocytes and DNA double-stranded break repair in various tissues. Dysregulation of this system leads to various pathological conditions including adaptive immunodeficiency. Meanwhile, the remaining lymphocytes are often aberrantly activated and lead to inflammations. We generated mutant mice carrying a missense mutation p.W447C in the DNA ligase IV (Lig4) gene, a critical component for NHEJ. Lig4W447C/W447C mice showed impaired DNA damage repair, growth retardation, and adaptive immunodeficiency. Furthermore, these mutant mice invariably developed lethal intestinal inflammation with marked infiltration of helper T (Th) cells　and macrophages. In the affected lesion, expression of Th1-related genes was upregulated. Notably, the inflammation was dependent on lymphocytes. Defective NHEJ due to a hypomorphic Lig4 gene mutation can lead to Th1-dependent intestinal inflammations under adaptive immunodeficiency.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、申請者が自験例に見出した遺伝子変異を持つマウスを作製・解析した。そのLig4低形成性変異マウス（Lig4W447Cホモ変異マウス）では、これまで当該機能分子の変異マウスでは認められなかった表現型、すなわち、獲得免疫不全下で獲得免疫の活性化を伴った潰瘍性大腸炎様の病態が発症することを新たに見出した。潰瘍性大腸炎やクローン病などの炎症性腸疾患では、免疫抑制剤やTNFα阻害剤などの生物学的製剤が広く使用されているが、治療に難渋する症例が多く、治療法は未だ確立していない。本研究により、原発性免疫不全症に加えて、難治性炎症性腸疾患の病態の解明、新たな制御手段に結び付く成果が期待される。