A novel mutation in IRAK2 results in immune dysregulation in systemic juvenile idiopathic arthritis (sJIA)

Abstract

Abstract Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory disease marked by innate immune activation with potentially fatal complications. Using trio exome sequencing, we identified a novel homozygous mutation in interleukin (IL)-1 Receptor Associated Kinase 2 (IRAK2) in a child with sJIA complicated by lung disease and hyperinflammation. IRAK2 is a serine/threonine kinase involved in IL-1 receptor and toll-like receptor signaling, leading to expression of pro-inflammatory genes. The patient displayed persistent elevation of IL-6, IL-8, and IL-18 and a strong interferon (IFN) stimulated gene (ISG) signature. To determine how the IRAK2 mutation contributes to the patient’s immunopathology, we used gene editing to create THP-1 cells homozygous for the mutation (THP-IRAK). Following 24 hours of lipopolysaccharide (LPS) treatment, RNA sequencing revealed that THP-IRAK cells display higher expression of IL-6, IL-18, and ISGs than wild type THP-1 cells (THP-wt). Gene set enrichment analysis of MSigDB hallmark sets identified LPS-induced upregulation of IFN signaling and cell cycle regulation related sets in THP-IRAK cells relative to THP-wt cells. Finally, LPS treatment led to higher secretion of IL-8 in THP-IRAK cells than in THP-wt cells. Together, these in vitro results recapitulate the pattern of inflammation observed clinically, which suggests that the IRAK2 mutation contributes to the pathophysiology of sJIA and nominates IRAK2 as a therapeutic target in sJIA.