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.
Acknowledgements
We thank the patients, their families, and the unaffected controls for their support during this study.
Funding
Q.Z. discloses support for this work from the National Natural Science Foundation of China [grant number 82225022 and 32321002], National Key Research and Development Program of China [grant number 2024YFC2511002], XPLORER PRIZE from New Cornerstone Science Foundation, Clinical Research Project for the Summit Program of Children’s Hospital of Chongqing Medical University [grant number CHCMU-2024-XKDF-1001], CAMS Innovation Fund for Medical Sciences (CIFMS) [grant number 2024-I2M-3-025] and State Key Laboratory Special Fund [grant number 2060204]. Z.L. discloses support for this work from the Basic Research Program of Jiangsu [grant number BK20243061]. X.Y. discloses support for this work from the National Natural Science Foundation of China [grant number 82394420, 82471844 and 82394424], the Hundred-Talent Program of Zhejiang University and the Key Technology Breakthrough Program of Ningbo Sci-Tech Innovation YONGJIANG 2035 [grant number 2024Z221]. C.Z. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82394424]. Y.J. discloses support for the research of this work from the National key research and development project of China [grant number 2021YFC2501302]. Y.W. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82402088], the Postdoctoral Fellowship Program of CPSF [grant number GZB20230635] and the China Postdoctoral Science Foundation [grant number 2024T170779 and 2024M752825]. S.W. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82402118]. L.G. discloses support for the research of this work from the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China [grant number LHDMY23H100005].
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Fei, Y., Liu, L., Ma, S. et al. IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73383-8
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DOI: https://doi.org/10.1038/s41467-026-73383-8
