Abstract
BackgroundIt is well known that interferon (IFN)-α is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-α producing cells are decreased or that their function is defective in patients with SLE. We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR)9 via a TLR9 ligand (CpG ODN2216) or SLE serum.MethodsThe concentrations of IFN-α were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-α were measured. The expression of IFN-α signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.ResultsAlthough there was no significant difference in serum concentration of IFN-α and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-α producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-α production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-α in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-α production, continuous TLR9 stimulation may lead to decreased production of IFN-α in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-α signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-α stimulation and had become desensitized to TLR signaling.ConclusionWe suggest that the persistent presence of endogenous IFN-α inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-α.
Highlights
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by generation of autoantibodies against nuclear DNA and/or nuclear proteins [1]
Results there was no significant difference in serum concentration of IFN-α and number of circulating plasmacytoid dendritic cells (pDCs) between systemic lupus erythematosus (SLE) patients and healthy control individuals, the IFN-α producing capacity of peripheral blood mononuclear cells (PBMCs) was significantly reduced in SLE patients
We suggest that the persistent presence of endogenous IFN-α inducing factors induces Toll-like receptor (TLR) tolerance in pDCs of SLE patients, leading to impaired production of IFN-α
Summary
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by generation of autoantibodies against nuclear DNA and/or nuclear proteins [1]. Over the past two decades numerous studies have suggested that interferon (IFN)-α may play a pathogenic role in SLE. This view is derived from the observation that IFN-α treatment in patients with nonautoimmune diseases, such as malignant tumors, induced anti-double-stranded DNA antibodies and occasionally resulted in the development of an SLE-like syndrome [3,4,5,6,7]. IFN-α levels correlate with anti-doublestranded DNA antibody production, complement activation, and IL-10 production, all of which are important indicators in SLE disease progression [9]. It is well known that interferon (IFN)-α is important to the pathogenesis of systemic lupus erythematosus (SLE). We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR) via a TLR9 ligand (CpG ODN2216) or SLE serum
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