Decades-long elevation of interferon-alpha can initiate and drive Sjogren syndrome II

Sjogren syndrome (SS) is a chronic inflammatory disease with no effective targeted treatments. There is a pressing need to identify targetable pathways which drive disease. Here we combine ultrasensitive detection of IFN-a with proteomic approaches in two cohorts including UK Biobank to demonstrate that IFN-a is elevated in the majority of individuals with SS, and this elevation can precede diagnosis by 15 years and persists for 30 years. We identify a distinct immunological phenotype associated with elevated IFN-a characterised by peripheral blood cytopenias, hypergammaglobulinaemia and SS-specific autoantibody formation. To address a causal role for chronic interferon elevation in initiating and driving these immunological features we created a novel model of systemic chronic IFN-a elevation upon overexpression of Ifna4 in conventional dendritic cells type 1 of mice. This model recapitulates the key IFN-a -associated features we identified in clinical studies and can be effectively treated by IFNAR1-blocking monoclonal antibodies. In summary chronically elevated IFN-a can initiate and drive immunopathological features of SS and represents a therapeutic target. Overall design: Transcriptomic investigation of whole spleen in wild-type and Clec9a-Cre IFNa4KI mice.