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Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

ABSTRACT: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon.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.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 (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 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.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. (Funded by the Dutch Arthritis Association and others.).

SUBMITTER: van Bon L

PROVIDER: S-EPMC4040466 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

van Bon Lenny L Affandi Alsya J AJ Broen Jasper J Christmann Romy B RB Marijnissen Renoud J RJ Stawski Lukasz L Farina Giuseppina A GA Stifano Giuseppina G Mathes Allison L AL Cossu Marta M York Michael M Collins Cindy C Wenink Mark M Huijbens Richard R Hesselstrand Roger R Saxne Tore T DiMarzio Mike M Wuttge Dirk D Agarwal Sandeep K SK Reveille John D JD Assassi Shervin S Mayes Maureen M Deng Yanhui Y Drenth Joost P H JP de Graaf Jacqueline J den Heijer Martin M Kallenberg Cees G M CG Bijl Marc M Loof Arnoud A van den Berg Wim B WB Joosten Leo A B LA Smith Vanessa V de Keyser Filip F Scorza Rafaella R Lunardi Claudio C van Riel Piet L C M PL Vonk Madelon M van Heerde Waander W Meller Stephan S Homey Bernhard B Beretta Lorenzo L Roest Mark M Trojanowska Maria M Lafyatis Robert R Radstake Timothy R D J TR

The New England journal of medicine 20131218 5

<h4>Background</h4>Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon.<h4>Methods</h4>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 compar ...[more]

PMID: 24350901

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Project description:BACKGROUND:Increased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD. METHODS:A total of 142 SSc-ILD patients from Scleroderma Lung Study (SLS) II were randomized in a double-blind, parallel-arm trial, to receive mycophenolate (MMF) for 2 years or oral cyclophosphamide (CYC) for 1 year followed by 1 year of placebo. Plasma CXCL4 levels were measured at baseline, 12 months, and 24 months in SLS II participants (N?=?136) and at a single time point in healthy controls (N?=?67). A mixed-effects model evaluated the relationship between change in CXCL4 levels and SSc-ILD progression. The primary outcome was the course of the forced vital capacity. RESULTS:Baseline CXCL4 levels were significantly higher in SSc-ILD patients compared with healthy controls (2699?±?1489 ng/ml vs 2233?±?1351 ng/ml (mean?±?SD); P?=?0.019). However, no significant correlations were identified between CXCL4 levels and extent of ILD at baseline, as measured by the forced vital capacity, diffusing capacity of carbon monoxide, or radiographic extent of ILD. Plasma CXCL4 decreased significantly from baseline to 12 months in all patients (CYC: P?<?0.001; MMF: P?=?0.006) with no between-treatment differences (CYC vs MMF). Patients with the largest decline in CXCL4 levels during the first 12 months had an improved course of forced vital capacity %-predicted from 12 to 24 months (P?=?0.040), even after adjusting for baseline disease severity and treatment arm assignment. CONCLUSIONS:Levels of CXCL4 were higher in patients with SSc-ILD compared with controls and decreased in all patients treated with immunosuppressive therapy. While CXCL4 levels were not correlated with extent of ILD at baseline, changes in CXCL4 at 12 months predicted future progression of SSc-ILD from 12 to 24 months. These findings suggest that intermediate-term changes in CXCL4 may have predictive significance for long-term progression of SSc-ILD in patients receiving immunosuppressive therapy. TRIAL REGISTRATION:ClinicalTrials.gov NCT00883129 . Registered 16 April 2009.

Project description:Lung fibrosis is a major cause of mortality and morbidity in systemic sclerosis (SSc). However, its pathogenesis still needs to be elucidated. We examined whether the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) might have a protective or a causative role in the lung fibrogenesis process. For this purpose we compared the BALF protein profile obtained from nine SSc patients with lung fibrosis (SScFib+) with that obtained from six SSc patients without pulmonary fibrosis (SScFib-) by two-dimensional gel electrophoresis (2-DE). Only spots and spot-trains that were consistently expressed in a different way in the two study groups were taken into consideration. In total, 47 spots and spot-trains, corresponding to 30 previously identified proteins in human BALF, showed no significant variation between SScFib+ patients and SScFib- patients, whereas 24 spots showed a reproducible significant variation in the two study groups. These latter spots corresponded to 11 proteins or protein fragments, including serum albumin fragments (13 spots), 5 previously recognized proteins (7 spots), and 4 proteins (3 spots) that had not been previously described in human BALF maps, namely calumenin, cytohesin-2, cystatin SN, and mitochondrial DNA topoisomerase 1 (mtDNA TOP1). Mass analysis did not determine one protein-spot. The two study groups revealed a significant difference in BALF protein composition. Whereas levels of glutathione S-transferase P (GSTP), Cu-Zn superoxide dismutase (SOD) and cystatin SN were downregulated in SScFib+ patients compared with SScFib- patients, we observed a significant upregulation of alpha1-acid glycoprotein, haptoglobin-alpha chain, calgranulin (Cal) B, cytohesin-2, calumenin, and mtDNA TOP1 in SScFib+ patients. Some of these proteins (GSTP, Cu-Zn SOD, and cystatin SN) seem to be involved in mechanisms that protect lungs against injury or inflammation, whereas others (Cal B, cytohesin-2, and calumenin) seem to be involved in mechanisms that drive lung fibrogenesis. Even if the 2-DE analysis of BALF did not provide an exhaustive identification of all BALF proteins, especially those of low molecular mass, it allows the identification of proteins that might have a role in lung fibrogenesis. Further longitudinal studies on larger cohorts of patients will be necessary to assess their usefulness as predictive markers of disease.

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Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

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Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

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