Background/Purpose:  Plasmacytoid Dendritic Cells (PDCs) are key immune cells involved with anti-viral responses due to their ability to produce large amount of type I IFN in response to Toll-like receptor (TLR)7 and TLR9 signaling. Several studies have reported that PDCs play a role in autoimmune diseases, including lupus, and inflammatory skin diseases such as psoriasis or dermatomyositis. Although the role of PDCs in Systemic Sclerosis (SSc) is less clear, several parallels studies suggest that mechanisms of innate immune dysfunction operating in SLE may also be important in SSc. Both diseases are associated with presence of autoantibodies to nucleic acid-binding proteins, e.g topoisomerase I and centromere and with increased expression of interferon-responsive genes by peripheral blood mononuclear cells, suggesting the participation of PDC in SSc. Recently, CXCL4 (Chemokine CXC motif ligand 4) was identified as a major protein secreted by PDC and as a biomarker of SSc as its level correlated with the presence of lung and skin fibrosis. The aim of this study is to investigate the role of PDC and the mechanisms by which these cells participate to the pathogenesis of SSc.

Methods:  Blood was obtained from 55 SSc patients or 14 healthy volunteers (HV) and PBMC isolated by density gradient. PDC were then isolated from PBMC by positive selection with BDCA4 magnetic beads or by cell sorting. PBMC was analyzed by flow cytometry. In addition, PDC were cultivated for 24h and IFNα and CXCL4 secretion were analyzed by ELISA.

Results:  We observed a decrease in the percentage of PDC in SSc PBMC as compared to HV PBMC (0.25±0.02 vs 0.51±0.09; p=0.003). SSc PDC spontaneously secreted excessive IFNa as opposed to HV (10-fold, p=0.03). On the other hand, no difference was observed in the expression of co-stimulatory molecules, CD86, CD83 and CD80 (46.5±10.5, 108.8±16.7 and 9.3±1.5 vs 54.9±5.9, 101±7.6, 18.4±4.9) as well as in the secretion of IL-6 in HV and SSc PDC (1.1±07 vs 8.3±3.1 pg/ml, p=0.2). We also confirmed an increased secretion of CXCL4 in SSc PDC (6903±662 in HV vs 17111±1855 pg/ml; p=0.001), which we showed is dependent on PI3Kδ. We also demonstrated that the increase of CXCL4 in patients is solely due to the secretion of this chemokine by PDC, and not by other cells in PBMCs. Moreover, we show that the CXCL4 and IFN pathways are intertwined in SSc as CXCL4 synergized with TLR9 signaling in PDC to induce enormous levels of type I IFN.

Conclusion:  Taken together our data provide evidence of a role of PDC in the pathogenesis of SSc. Decrease in number of PDC in SSc blood suggest an activation of PDC and their migration to the site of disease, probably the skin. We also show that SSc PDC exhibit a non-mature state, with high production of IFNα and low expression of maturation molecules. CXCL4 secretion is dependent on PI3Kδ pathway and contribute to increased IFNa secretion through TLR9 activation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasmacytoid-dendritic-cells-are-activated-in-systemic-sclerosis-and-contribute-to-the-disease-by-inducing-ifn%ce%b1-and-cxcl4/