In the present study, we demonstrate for the first time: i) the presence of significant levels of extracellular IFI16 protein in the sera of patients affected by systemic autoimmune diseases, including SSc, SjS, SLE and RA but not in non-SLE GN as compared to healthy controls, and ii) that the extracellular IFI16 exerts biological effects on endothelial cells upon binding to a specific cell surface receptor. Here, IFI16 is linked to systemic lupus erythematosus.