Type I interferon in organ-targeted autoimmune and inflammatory diseases

Abstract

A significant role for IFNα in the pathogenesis of systemic lupus erythematosus is well supported, and clinical trials of anti-IFNα monoclonal antibodies are in progress in this disease. In other autoimmune diseases characterized by substantial inflammation and tissue destruction, the role of type I interferons is less clear. Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus. In both of those diseases, presence of the interferon signature has been associated with more significant clinical manifestations. At the same time, evidence supports an anti-inflammatory and beneficial role of IFNβ locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNβ. As can also be proposed for type I diabetes mellitus, type I interferon appears to contribute to the development of autoimmunity and disease progression in multiple autoimmune diseases, while maintaining some capacity to control established disease - particularly at local sites of inflammation. Recent studies in both rheumatoid arthritis and multiple sclerosis suggest that quantification of type I interferon activity or target gene expression might be informative in predicting responses to distinct classes of therapeutic agents.

Figure 1

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.