IRAK2 deficiency causes a new immune dysregulation disorder
Fei, Y.; Liu, L.; Ma, S.; Wang, S.; Lu, M.; Xue, J.; Jin, Y.; Wang, Y.; Sun, X.; Chen, X.; Han, X.; Zhang, C.; Guo, L.; Zhang, J.; Zhong, H.; Wen, L.; Yu, X.; Zhou, Q.; Liu, Z.
Show abstract
Interleukin 1 receptor-associated kinase 2 (IRAK2) plays a critical role in immune response by participating in the formation of the Myddosome complex in Toll-like receptor (TLR) signaling pathways. Here, we identified a loss-of-function mutation (IRAK2-{Delta}ex2) in the IRAK2 gene in three patients, presenting with immune dysregulation, including systemic lupus erythematosus (SLE) and autoinflammatory disease. This mutation leads to the skipping of exon 2 in IRAK2, disrupting its interaction with IRAK4 and impairing the activation of nuclear factor kappa B (NF-{kappa}B) and mitogen-activated protein kinase (MAPK) signaling pathways via Myddosome. The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. Our study suggests that IRAK2 deficiency results in immune dysregulation due to compromised TLR signaling and activated IFN signaling primarily in monocyte-macrophage lineage. One Sentence SummaryA new immune dysregulation disorder caused by a loss-of-function mutation in the IRAK2 gene, which disrupts TLR signaling via Myddosome, results in impaired NF-{kappa}B activation and upregulated type I interferon responses.
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