IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses
Year: 2026
Type: article
Study design: Observational Study
Abstract: Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for the Myddosome complex formation downstream of Toll-like receptors. We identify twelve patients with a homozygous loss-of-function copy number variant in IRAK2, designated IRAK2-∆ex2. Most patients present with recurrent infections, autoantibody production, and gastrointestinal ulceration. Two patients were clinically diagnosed with primary immunodeficiency, while the majority fulfill diagnostic criteria for autoimmune or autoinflammatory diseases. The IRAK2-∆ex2 protein fails to interact with IRAK4, leading to impaired activation of nuclear factor kappa B signaling via the Myddosome complex. An elevated type I interferon signature is observed in the patients, which is confirmed in bone marrow-derived macrophages from knock-in mice and knockout cell lines. Mechanistically, our data are consistent with engagement of a TRIF-dependent interferon pathway. Baricitinib attenuates the elevated interferon signature in patient-derived cells ex vivo and cell lines. Here, we show IRAK2 deficiency as a monogenic immune dysregulation disorder. Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for Myddosome complex formation downstream of most Toll-like receptors. Here, the authors show a loss-of-function copy number variant of IRAK2 associated with immunodeficiency, autoimmunity, and autoinflammation, which disrupts IRAK2 interaction with IRAK4 and further downstream Myddosome formation, accompanied by enhanced interferon responses.
Source: Nature Communications
Authors: Yudie Fei, Lin Liu, Shuangyue Ma, Ying Jin, Shihao Wang, Liang Zhang, Jun Yang, Yi Liu, Meiping Lu, Jing Xue, Jingyi Li, Xiang Chen, Jun Wang, Yuhao Yao, Chenlu Liu, Jiahui Zhang, Xu Han, Jinjian Fu, Zhijuan Kang, Yusha Wang, Xiangwei Sun, Changming Zhang, Tingyan He, Zhihui Liu, Zhihui Liu, Li Guo, Chengshun Chen, Hongmei Zhao, Xingjian Gao, Hua Zhong, Lihong Wen, Xiaomin Yu, Zhihong Liu, Zhihong Liu, Qing Zhou
Institutions: Nanjing General Hospital of Nanjing Military Command, Zhejiang University, Nanjing University, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Nanjing Medical University, Wenzhou Medical University, Zhoushan Hospital, Central South University, Hunan Children's Hospital, University of South China, Shenzhen Children's Hospital, Sichuan University, West China Hospital of Sichuan University, Children's Hospital of Zhejiang University, Second Affiliated Hospital of Zhejiang University, Army Medical University, Sir Run Run Shaw Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7161965328