OP0107 HETEROZYGOUS MUTATIONS IN COPA ARE ASSOCIATED WITH ENHANCED TYPE I INTERFERON SIGNALLING

Abstract

Background Heterozygous mutations in COPA, encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy (SAVI). Mutations were originally described to cause endoplasmic reticulum (ER) stress and priming of a T helper 17 response. More recently, increased transcription of interferon (IFN)-stimulated genes (ISGs) was reported in blood circulating cells of affected individuals. However, the precise pathophysiology of this disease remains unclear. Objectives To better decipher the mechanism of COPA syndrome. Methods We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in COPA. We assessed type I IFN status by IFNα ultra-sensitive digital quantification in plasma, STAT1 phosphorylation and RNA expression of ISGs in whole blood from patients. In vitro assays also were performed in HEK293T and THP-1 cells to study IFN signalling in the context of COPA mutations. Results We observed commonalities in the lung pathology between COPA and SAVI, as well as an IFN signature, raised levels of IFNα protein in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model of HEK293T, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids. In THP-1 cells, short hairpin RNA knockdown of COPA induced IFN signalling that was abrogated in the absence of STING. Conclusion Our data suggest that mutations in COPA lead to constitutive activation of type I IFN signalling through STING. Based on these results, one patient has been treated with the JAK1/2 inhibitor ruxolitinib for the last 12 months. How COPA interacts with ER-resident STING remains to be investigated.