Variability in primary Sjögren's syndrome is driven by interferon alpha, and genetically associated with the class II HLA DQ locus

International audienceObjective: Primary Sjögren's syndrome (pSS) is the second most frequent systemic autoimmune disease affecting 0.1% of the general population. To characterize the molecular and clinical variability across pSS patients, we integrated transcriptomic, proteomic, cellular and genetic data with clinical phenotypes in a cohort of 351 pSS patients.Methods: Blood transcriptomes and genotypes of 351 pSS patients from a multi-center prospective clinical cohort were analyzed. Replication of the transcriptomic results was performed using 3 independent cohorts (n=462 patients). Circulating IFN-alpha (IFNɑ) and IFN-gamma (IFNγ) protein concentrations were determined using digital ELISA.Results: Transcriptomic analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients. This finding was replicated in three independent cohorts. As gene expression analysis did not discriminate between type I and II interferons, we applied digital ELISA to demonstrate that the IFN transcriptomic signature was driven by circulating IFNɑ, and not IFNγ, protein levels. IFNɑ protein levels, detectable in 75% of patients, were significantly associated with clinical and immunological features of disease activity at enrollment, and with increased frequency of systemic complications during the 5-year follow-up. Genetic analysis revealed a significant association between IFNɑ protein levels, a MHC-II haplotype and anti-SSA antibody. Additional cellular analysis revealed that a MHC-II HLA-DQ locus acts through upregulation of HLA II molecules on conventional DCs.Conclusions: The present analysis identified the predominance of IFNα as driver of pSS variability and revealed an association with HLA gene polymorphisms