IRAK2 deficiency causes a new immune dysregulation disorder

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.