IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses.

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.