Objective. Microarray analyses of peripheral blood leukocytes have shown that patients with systemic lupus erythematosus express increased levels of type I interferon (IFN)-regulated genes. In this study we examined gene expression by peripheral blood mononuclear cells (PBMCs) from patients with systemic sclerosis (SSc) to better understand the dysregulation of the immune system in this disease. Methods. PBMC gene expression was analyzed by microarray and confirmed by real-time polymerase chain reaction (PCR). Surface protein expression of

No abstract

T helper (Th) cells play a central role in systemic lupus erythematosus (SLE). Activated autoreactive Th cells provide the help required for autoreactive B cells to differentiate and produce pathogenic autoAbs. Both autoAb-containing immune complexes and direct effects of inflammatory Th cells promote tissue injury and organ damage. In SLE, triggering of plasmacytoid dendritic cell (pDC) Toll-like receptors by autoimmune complexes containing nucleic acid autoantigens stimulates pDC secretion of high levels of type I interferons (IFN-alpha/beta). Study of SLE patients and murine disease models implicate these type I IFNs as key disease effectors. However, the role of pDC-derived type I IFNs in regulating the inflammatory function of Th cells in SLE is unknown. Although, type I IFNs are classically considered to promote Th1-mediated inflammation, they can also act as potent inhibitors of both Th1 and Th17 inflammatory cell responses. Work of ourselves and others leads us to hypothesize that if initiated during stages of SLE when Th cell-mediated tissue inflammation is absent or minimal, such as early in the disease or during periods of remission, type I IFN neutralization will disrupt the cycle of systemic autoimmune induction and disease. However, if initiated during advanced stages of disease when there is substantial ongoing Th1 (and possibly Th17) cell-mediated inflammation, targeting type I IFNs will exacerbate the Th cell-mediated inflammatory disease and thus potentiate end-organ damage and destruction. This has important implications for the application of the numerous anti-type I IFN therapies currently under development for SLE treatment.

Inflammatory, IFN‐γ‐secreting Th1 cells are implicated in mediating serious forms of systemic lupus erythematosus (SLE), including nephritis and CNS lupus. In SLE, triggering of plasmacytoid DC (pDC) Toll‐like receptors (TLRs) by circulating anti‐nucleic acid‐containing autoimmune complexes stimulates pDC secretion of high levels of type I interferon (IFN) (IFN‐α/β). Study of both human and murine lupus disease strongly implicates these IFNs as key disease effectors. However, the role of pDC‐derived type I IFN in regulating the function of inflammatory Th cells in SLE is unknown. We and others have shown that, although classically considered to promote Th1 cell mediated inflammation, type I IFN can also function as a potent inhibitor of both inflammatory Th1 and Th17 responses. We employed the pan‐type I IFN neutralizing reagent, B18R, to investigate how type I IFN regulate Th cell responses in SLE. Recent observations indicate a subset of SLE patient sera that inhibits IFN‐γ 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, LT and IL‐17, while negatively correlating with IL‐10 secretion. Remarkably, the ability of SLE patient serum to inhibit IFN‐γ secretion in a type I IFN dependent manner correlates with positive serum Sm and RNP titers. 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.

Type I interferons (IFNs) can have contrasting effects on adaptive Th1 responses. IFN-α/β are well recognized anti-viral agents that promote anti-viral Th1 immune responses. In contrast, IFN-β therapy provides a beneficial effect in multiple sclerosis patients, in part, by suppressing Th1 type autoimmune responses. In systemic lupus erythematosus (SLE), autoimmune complex-induced, plasmacytoid dendritic cell (pDC)-derived IFN-α is thought to be a major disease effector. To investigate how type I IFNs regulate Th cell autoimmune inflammatory responses in SLE, we established a model of human peripheral blood mononuclear cell (PBMC) stimulation. In this model, the effects of continuous type I IFN exposure are mimicked by pretreating PBMC with either recombinant type I IFN or the pDC-TLR9 agonist, CpG-A, and stimulation of autoreactive Th cells is mimicked by stimulation with the superantigen, SEA. Type I IFN neutralization with B18R, a vaccinia virus-derived soluble type I IFN receptor, is used to specifically identify effects of CpG-A-induced type I IFN. Our results indicate that pretreatment with rIFN-α, rIFN-β, or CpG-A-induced type I IFN inhibits SEA-stimulated IFN-γ secretion by healthy donor PBMC. Preliminary experiments demonstrate that, when compared to serum from control individuals, some SLE patient sera similarly inhibit IFN-γ secretion by normal PBMC. In addition, co-pretreatment of PBMC with B18R and serum from several SLE patients reveals a type I IFN-mediated inhibitory effect on IFN-γ secretion. Our findings suggest that in SLE circulating type I IFNs may suppress Th cell-mediated tissue injury by inhibiting inflammatory cytokine-secreting autoreactive Th cells