IFNα is predominantly a product of the peripheral immune system. In systemic lupus erythematosus (SLE), IFNα is produced at high levels and has systemic effects on multiple immune system pathways, promoting autoimmunity and inflammation. A more modest level of IFNα might also contribute to autoimmunity in type I diabetes mellitus (DM), multiple sclerosis (MS) and rheumatoid arthritis (RA), as demonstrated by data from murine models and an interferon-inducible gene signature in blood. IFNβ is produced in small amounts by myeloid cells but probably has its greatest impact locally where it is produced by fibroblasts and stromal cells. Type I interferon-inducible gene products, such as IL-10 and IL-1 receptor antagonist (IL-1ra), produced locally can blunt inflammation.