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New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production.

ABSTRACT: Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFN?), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFN? supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell-targeting antibody-mediated depletion strategies, which do not eliminate autoantibody-secreting plasma cells. Recent clinical trials testing the efficacy of IFN? neutralization in SLE have delivered disappointing results, with primary endpoints not being met or with minimal improvements, while studies evaluating antibody therapy targeting the type I IFN receptor was more successful and is currently being tested in phase III clinical studies. As many studies have supported the idea that plasmacytoid dendritic cells (pDCs) are the main source of IFN? in SLE, specifically targeting pDCs in SLE represents a new therapeutic option. Murine models suggest pDC ablation effectively ameliorates or reduces lupus-like disease development in spontaneous models of lupus and pre-clinical and phase I clinical trials support the safety of such a therapy in humans. Here we review animal studies and the current status of clinical trials targeting IFN?, type I interferon receptor and pDCs in SLE.

SUBMITTER: Davison LM

PROVIDER: S-EPMC5804747 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production.

Davison Laura M LM Jorgensen Trine N TN

Journal of clinical & cellular immunology 20171220 6

Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNα), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNα supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell-targeting antibody-mediated depletion strat ...[more]

PMID: 29430334

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Project description:BackgroundIt is well known that interferon (IFN)-alpha is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-alpha 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-alpha 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-alpha were measured. The expression of IFN-alpha 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-alpha and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-alpha producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-alpha production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-alpha in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-alpha production, continuous TLR9 stimulation may lead to decreased production of IFN-alpha in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-alpha stimulation and had become desensitized to TLR signaling.ConclusionWe suggest that the persistent presence of endogenous IFN-alpha inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-alpha.

Dataset Information

New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production.

Publications

New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production.

Similar Datasets

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