[1377] Type I Interferons: Regulators of Inflammatory T Helper Cell Responses in SLE

AJ Mangini, T Nagai, A Ozonoff, MJ Fritzler, R Lafyatis, J Maguire van Seventer. Boston University School of Medicine, Boston; Boston University School of Public Health, Boston; University of Calgary School of Medicine, Calgary, Canada

Background: Type I Interferon (IFN), and , are well recognized anti-viral agents that induce potent inflammatory T helper cell 1 (Th1) responses. Their effects on Th cell activity however, can be contrasting. As observed in multiple sclerosis patients, the beneficial effect of IFN- therapy is partly due to the suppression of the Th1 type autoimmunity. In Systemic Lupus Erythematosus (SLE), the triggering of plasmacytoid dendritic cell (pDC) toll-like receptors (TLRs) by circulating anti-nucleic acid-containing autoimmune complexes stimulates pDCs to secrete high levels of type I IFNs. Study of both human and murine lupus disease strongly implicates type I IFNs as key disease effectors. However, while inflammatory, interferon (IFN)--secreting Th1 cells are implicated in mediating serious forms of SLE, including nephritis and CNS lupus, the role of pDC-derived type I IFNs in regulating the function of these inflammatory Th cells in SLE is unknown.
Design: To investigate how type I IFNs regulate Th cell autoimmune inflammatory responses in SLE, we established an in vitro model of human peripheral blood mononuclear cell (PBMC) stimulation to mimic the effects of continuous type I IFN exposure.
Results: Our results indicate a subset of SLE patient sera that, when compared to normal donor sera, inhibits IFN- secretion by superantigen-stimulated healthy donor PBMC in a type I IFN-dependent manner. This effect positively correlates with PBMC secretion of the Th cell inflammatory cytokines, lymphotoxin (LT) and interleukin (IL)-17, while negatively correlating with IL-10 secretion. Remarkably, the ability of SLE patient serum to inhibit IFN- secretion in a type I IFN dependent manner correlates with positive serum titers of Sm and RNP, two anti-nuclear antibodies (ANAs) that occur in some SLE patients.
Conclusions: Our findings suggest that in SLE patients with significant serum type I IFN activity, type I IFN blockade may exacerbate Th cell-mediated autoimmune inflammation by inhibiting inflammatory cytokine-secreting autoreactive Th cells. Moreover, they suggest that specific ANA profiles can potentially be used as a biomarker to identify patients in which such a negative outcome is likely to occur.
Category: Kidney (does not include tumors)

Tuesday, March 10, 2009 1:00 PM

Poster Session IV # 190, Tuesday Afternoon