Background/Purpose: Lung disease (LD) is poorly understood complication of Still’s disease with high fatality. HLA-DRB1*15 is a strong risk factor for the development of this complication, but it is not present in all patients. It has been suggested that interferons may be involved in Still’s-LD, but how they are involved remains unclear. Here, we describe a possible monogenic case of Still’s caused by a novel variant in IL-1 Receptor Associated Kinase 2 (IRAK2). IRAK2 is a serine/threonine kinase involved in IL-1 receptor and toll-like receptor signaling, which functions upstream of NF-κB and type I interferon signaling.

Methods: Participants were enrolled in a NIH natural history study of Still’s disease. Trio exome sequencing was performed. Whole blood expression of 28 interferon (IFN) -stimulated genes (ISG) was quantified with custom NanoString arrays and expressed as a normalized score. Serum cytokine levels were measured by Olink® Target 48 Cytokine panel. HEK-293T cells were transfected with the patient’s variant (Q127H), as well as with a known loss of function (LOF, R43Q), and wild type (WT) IRAK2 variants. NF-κB activation was measured in a luciferase assay. THP1 cells were generated by CRISPR-Cas9 to be homozygous for Q127H IRAK2. CXCL8 was measured by ELISA. Gene set enrichment analysis (GSEA) using MSigDB Hallmark-50 gene set was performed on WT and Q127H by bulk RNA sequencing following 24 hour LPS stimulation.

Results: A 10-year-old girl with consanguineous parents was diagnosed with Still’s disease at 8 years of age. Her course was complicated by severe disease refractory to multiple biologics, recurrent episodes of macrophage activation syndrome (MAS) and LD with pulmonary hypertension. She did not carry HLA-DRB1*15, but instead carried an HLA-DRB1*11 allele. Trio sequencing identified a novel, homozygous IRAK2 variant (Q127H). Compared to our cohort of consecutive Still’s disease patients, the patient displayed persistent elevation of IL-6, CXCL8, and IL-18, as well as a strong ISG signature; her mother also exhibited a strong ISG signature. Overexpression of Q127H in HEK-293T cells resulted in greater NF-kB at baseline and after IL1β stimulation (100 ng) for 6 hours. Mutant THP1 cells demonstrated increased secretion of CXCL8 following stimulation with LPS for 24 or 28 hours. GSEA revealed that in response to 24 hour LPS stimulation, the Q127H THP1 cells displayed markedly stronger induction of IFN signaling, mTORC1 signaling and cell cycle regulatory gene sets, relative to WT THP1 cells.

Conclusion: Here, we describe a novel, homozygous mutation in IRAK2 in a patient with severe Still’s disease and LD. This is the first human inflammatory disease linked to IRAK2. IRAK2 Q127H is a gain of function variant that leads to hyperactivation of NF-κB and type I interferon pathways, as observed in the patient and recapitulated in several in vitro models. This reinforces the hypothesis that high impact genetic variation is contributing to severe Still’s disease, in this case through enhanced production of type I interferons. This finding could allow for the development of a mouse model of Still’s disease, and help to clarify the pathophysiology of Still’s-LD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-variant-in-irak2-results-in-immune-dysregulation-in-systemic-juvenile-idiopathic-arthritis-sjia/