The role of type I interferons in T helper cell inflammatory responses in systemic lupus erythematosus

Type I interferons (IFNs) can mediate both positive and negative regulatory effects on inflammatory T helper (Th) cell function depending on the timing and duration of exposure. In systemic lupus erythematosus (SLE), the clinical and cellular manifestations of excessive production of IFN-alpha mark this cytokine as a key disease effector. Despite development of type I IFN-targeting therapeutics, the immunoregulatory activity of type I IFNs on Th cell responses in SLE is unknown. The goal of this research is to identify the role of type I IFNs in regulating inflammatory Th cell responses in SLE.;Our results indicate that in some SLE patients circulating type I IFNs play a protective role by negatively regulating inflammatory Th cell responses. Specifically, both circulating IgG autoimmune complexes and endogenous IFN-alpha in SLE patient sera were shown to block the effector functions of Th1 and Th17 cells within healthy donor peripheral blood mononuclear cells by down-regulating secretion of inflammatory cytokines, IFN-gamma, interleukin (IL)-17, lymphotoxin (LT) and tumor necrosis factor alpha (TNF-alpha), while elevating anti-inflammatory, IL-10 secretion. The significant correlation between this anti-inflammatory effect and the presence within sera of specific anti-dsDNA, anti-RNP and anti-Sm autoantibodies indicates a potential disease biomarker to identify patients in which therapies that target type I IFN activity could potentiate Th cell IFN-gamma/1L-17-mediated autoimmune inflammation.;Results indicate that the absence of type I IFN signaling in genetic type I IFN receptor (IFNAR) deficient mice inhibits the onset/progression of autoimmune disease in the gld.apoE-/- murine model of lupus-like autoimmune disease and associated atherosclerosis. Specifically, compared to gld.apoE-/- mice, gld.apoE-/- .ifnar-/- mice had decreased splenomegaly, lymphadenopathy, lymphoproliferation, hypergammaglobinemia, and serum anti-dsDNA levels, and markedly delayed development of glomerulonephritis. In contrast, type I IFN deficiency promoted atherosclerosis as indicated by an increase in aortic lesions and tissue endothelin-1 expression.;Collectively these results suggest a multifaceted role for type I IFNs in SLE. They indicate a potential beneficial effect of Type I IFN targeting early in disease, while suggesting the potential for deleterious effects if type I IFN blockade is initiated in patients with advanced disease involving substantial inflammatory Th cell activity and/or cardiovascular complications.