Type I interferon in systemic autoimmune diseases

Th e hypothesis that type I interferon plays a central role in the pathogenesis of systemic lupus erythematosus (SLE) has gained growing support in recent years [1-4]. Th e early data from the 1970s demonstrating increased functional interferon activity in lupus patient sera have been confi rmed and extended using current technologies that permit detection of the broad gene expression program induced by type I interferons [5-8]. Expression of an interferon signature – refl ecting expression of often more than 100 type I interferon-inducible genes in peripheral blood mononuclear cells (PBMC) – is also seen in highly related syndromes characterized by systemic autoimmunity, including Sjögren’s syndrome [9]. In addition, clinical observations from patients treated with recombinant IFNα for control of hepatitis C infection or malignancy indicate that in some individuals, possibly determined by their harboring genetic susceptibility factors that aug ment response to interferon, auto antibodies character istic of SLE can develop [10,11]. Occasion ally clinical features that represent at least four of the American College of Rheumatology classifi cation criteria for diag nosis of SLE develop in those patients. Th e occurrence of clinical syndromes more charac teristic of infl ammatory diseases distinct from SLE in patients treated with therapeutic IFNα has gained less attention. Nonetheless, numerous case reports and case series describe infl ammatory arthritis, multiple sclerosis (MS) or diabetes that develops during the course of interferon therapy [12-15]. As in the case of the lupus-like syn dromes, the capacity of IFNα to promote those diseases that are typically considered to have strong infl am matory components suggests that type I interferon might also play a pathogenic role in diseases such as rheumatoid arthritis (RA), MS or type I diabetes mellitus (DM). Th e data supporting increased expression of IFNα and interferon-inducible genes in those diseases is less well developed than in the prototype systemic autoimmune disease SLE or in Sjögren’s syndrome, which shares some autoantibody specifi cities and immune system alterations with SLE [16]. Confusing our understanding of the role of type I interferons in these other diseases that are characterized by systemic autoimmunity as well as pathology and clinical manifestations focused on an organ system (RA: diarthodial joints; MS: myelin sheath in the central nervous system; and DM: insulin-producing β cells in the pancreas) is the fact that type I interferons have been Abstract