OP0107 HETEROZYGOUS MUTATIONS IN COPA ARE ASSOCIATED WITH ENHANCED TYPE I INTERFERON SIGNALLING. (June 2019)

• Record Type: Journal Article
• Authors: Frémond, Marie-Louise; Lepelley, Alice; Uggenti, Carolina; Martin-Niclos, Maria José; Depp, Marine; Bondet, Vincent; Duffy, Darragh; Rice, Gillian I; Brennan, Mary; Thumerelle, Caroline; Boulisfane, Siham; Legendre, Marie; Amselem, Serge; Molina, Thierry; Nathan, Nadia; Crow, Yanick
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 127
• Page End: 127
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.4158
• Languages: English
• ISSNs: 0003-4967

Abstract

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. References: [1] Watkin et al, Nat Genet2015;47:654-60. [2] Volpi et al, Clin Immunol2018;187:33-36. Disclosure of Interests: None declared