Elucidation of the mechanism of human antibody production by identifying causative genes for primary antibody deficiency

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07814
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: IMAI Kohsuke 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): 2018-04-01 – 2021-03-31
• Keywords: 抗体産生 / 免疫記憶 / 原発性免疫不全症 / 形質細胞 / B細胞 / DNAメチル化 / 遺伝子再構成 / エクソーム解析

Outline of Final Research Achievements

Common variable immunodeficiency (CVID) is a disease in which antibody production is not possible due to a single gene abnormality. In this study, through the analysis of novel CVID patient due to complete APRIL deficiency, we found that APRIL is responsible for lifelong immunological memory by maintaining memory B cells and plasma cells, and proposed a new CVID subclassification method using serum BAFF and APRIL. In addition, through the analysis of patients with PNKP deficiency and DNMT3B mutated ICF syndrome, which were found by whole exome sequencing, we studied the mechanisms by which each molecule is involved in B cell receptor gene rearrangement and memory B cell differentiation and maintenance.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

APRIL欠損症の発見と病態の解明から、抗体産生へのAPRILの役割がわかり、組換えAPRILの臨床応用への可能性が示唆された。抗体産生不全症約200例について、記憶B細胞、形質細胞、IgG/A/M/E、血漿APRIL, BAFFを用いた分類を行った。XLA患者では全例BAFF高値・APRIL正常範囲であり、その他の抗体産生不全症患者、自己免疫疾患患者を、BAFF and/or APRIL高値と正常の4群にわけることが可能であった。また、抗体産生不全症を中心とした175例でのExome解析の結果、約1／3は既知遺伝子異常が同定されたが、残り2／3は原因不明であり、今後の研究の進展が望まれる。