Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis.

Background Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. Methods We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. Results Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (\ub1SD) level of CXCL4 in patients with systemic sclerosis was 25,624\ub12652 pg per milliliter, which was significantly higher than the level in controls (92.5\ub177.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346\ub11011 pg per milliliter), ankylosing spondylitis (1368\ub11162 pg per milliliter), or liver fibrosis (1668\ub11263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. Conclusions Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

Item does not contain fulltextThere is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of /= 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity

Rotigotine transdermal patch and sleep in Parkinson’s disease: where are we now?

Abstract A wide range of sleep dysfunction complicates Parkinson’s disease during its course from prodromal to palliative stage. It is now increasingly acknowledged that sleep disturbances are thus integral to the disease and pose a significant burden impacting on quality of life of patients. Sleep fragmentation, restless legs syndrome, nocturia, and nocturnal pain are regarded as one of the main components of night-time sleep dysfunction with possible secondary impact on cognition and well-being. The role of dopaminergic therapies, particularly using a continuous drug delivery strategy in managing some of these sleep issues, have been reported but the overall concept remains unclear. This review provides an overview of several aspects of night-time sleep dysfunction in Parkinson’s disease and describes all available published open-label and blinded studies that investigated the use of rotigotine transdermal patch targeting sleep. Blinded studies have suggested beneficial effects of rotigotine transdermal patch on maintenance insomnia and restless legs syndrome in Parkinson’s disease patients. Open-label studies support these observations and also suggest beneficial effects on nocturia and nocturnal pain