Characterization of molecular pathogenesis of primary immunodeficiency focusing on host susceptibility to viruses

原发性免疫缺陷的分子发病机制表征，重点关注宿主对病毒的易感性

• 批准号: 22H03041
• 负责人: 岡田 賢
• 金额: $ 11.23万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22H03041/
• 关键词: 原発性免疫不全症; ウイルス; I型インターフェロン; STAT1; 易感染性; 自己抗体; 遺伝子異常

原発性免疫不全症（PID）は、宿主免疫の障害により多彩な病原体に対して易感染性を示す疾患で、その多くは単一遺伝子の異常により発症する。過去に400を超える責任遺伝子が同定され、それに基づいて病態解明が行われてきた。その結果、遺伝子診断はPID患者の診断確定のみならず、治療法の選択にも重要な役割を担うようになった。しかし、PID患者の約半数は原因遺伝子が不明であり、未知の責任遺伝子の存在、網羅的ゲノム解析で検出困難な有害変異、ゲノム異常以外の要因などが病態形成に関与すると推測されている。本研究では、I型インターフェロン（IFN）に着目してPIDの病因病態解明に取り組んだ。その結果、I型IFN過剰状態を示す患者においてRelA遺伝子異常を同定することができた。RelAは、その半量不全によりベーチェット病様の症状を示すことが知られていたが、同定した患者は既報告例と比較して重篤な症状を示した。詳細な機能解析を行ったところ、従来の半量不全と異なり同定した変異は優性阻害効果を示すことが判明し、新規のPIDとして『優性阻害効果によるRelA異常症』の疾患概念を示すことができた。研究内容は、近日中に論文化を予定している。並行して、STAT1機能獲得型変異の背景に存在する分子病態の解析を行った。STAT1機能獲得型変異は、その過剰なリン酸化を背景に過剰なシグナル伝達を示す。詳細な解析の結果、STAT1機能獲得型変異はホスファターゼによる脱リン酸化に抵抗性を示すことが判明した。今後、得られた結果の検証作業を行うとともに、論文執筆中にも取り組む予定である。

Primary immune insufficiency (PID), host immune disorders, colorful pathogens, susceptibility to infection, and multiple symptoms. In the past 400 years, we have been able to make sure that the child is the same as the doctor, and the doctor will explain the state of the disease. According to the results of the study, the patients with severe acute respiratory syndrome (PID) were confirmed and the treatment methods were selected for the treatment of critical care. About half of the patients with chronic hepatitis and PID have unknown causes, unknown children exist, network health problems are found to be harmful, and diseases are often caused by illness. The purpose of this study was to determine the etiology and pathology of patients with PID in this study. The etiology and pathology of the patients were analyzed in this study. The etiology and pathology of type I and type I were analyzed in this study (IFN). The results of the test and the type I IFN filter status show that the patients often have the same symptoms as those of the patients with chronic RelA syndrome. The symptoms of RelA and semiincomplete diseases are more severe than those of patients with the same conditions. The machine can analyze the concept of the disease, half of the data, the same as the diagnosis of the disease, and the new concept of PID disease, the common disease of RelA, and the concept of disease. The content of the study, the recent discussion on culture and the definition of culture. There is molecular pathologic analysis in the background of concomitant diagnosis and STAT1 acquired disease. The STAT1 machine can be used to achieve the desired results. The background of the acidification test has reached the demonstration level. The results were analyzed and the results were analyzed by STAT1 machine. The results showed that the resistance was detected by biochemical analysis. In the future, you will get the results that you will not be able to do so. In the course of writing, you will be able to determine the performance of the computer system.

项目成果

Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases

• DOI: 10.1007/s10875-022-01396-1
• 发表时间: 2022-11
• 期刊: Journal of Clinical Immunology
• 影响因子: 9.1
• 作者: Rintaro Ono;M. Tsumura;S. Shima;Yusuke Matsuda;K. Gotoh;Yurina Miyata;Y. Yoto;Dan Tomomasa;Takanori Utsumi;H. Ohnishi;Zenichiro Kato;N. Ishiwada;A. Ishikawa;T. Wada;H. Uhara;R. Nishikomori;D. Hasegawa;S. Okada;H. Kanegane

Mendelian susceptibility to mycobacterial diseases

孟德尔对分枝杆菌疾病的易感性

• 发表时间: 2023
• 作者: Ono R;Tsumura M;Shima S;Matsuda Y;Gotoh K;Miyata Y;Yoto Y;Tomomasa D;Utsumi T;Ohnishi H;Kato Z;Ishiwada N;Ishikawa A;Wada T;Uhara H;Nishikomori R;Hasegawa D;Okada S;Kanegane H.;Satoshi Okada
• 通讯作者: Satoshi Okada

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia.

• DOI: 10.1084/jem.20220131
• 发表时间: 2022-08-01
• 期刊: The Journal of experimental medicine

Defective type I interferon in severe COVID-19

严重 COVID-19 中 I 型干扰素缺陷

• 发表时间: 2023
• 作者: Ono R;Tsumura M;Shima S;Matsuda Y;Gotoh K;Miyata Y;Yoto Y;Tomomasa D;Utsumi T;Ohnishi H;Kato Z;Ishiwada N;Ishikawa A;Wada T;Uhara H;Nishikomori R;Hasegawa D;Okada S;Kanegane H.;Satoshi Okada;Satoshi Okada
• 通讯作者: Satoshi Okada

先天性免疫異常症の新たな遺伝子診断法により診断効率を向上

先天性免疫疾病基因诊断新方法提高诊断效率