• Lenny van Bon, Alsya J Affandi, Jasper Broen, Romy B Christmann, Renoud J Marijnissen, Lukasz Stawski, Giuseppina A Farina, Giuseppina Stifano, Allison L Mathes, Marta Cossu, Michael York, Cindy Collins, Mark Wenink, Richard Huijbens, Roger Hesselstrand, Tore Saxne, Mike DiMarzio, Dirk Wuttge, Sandeep K Agarwal, John D Reveille, Shervin Assassi, Maureen Mayes, Yanhui Deng, Joost P H Drenth, Jacqueline de Graaf, Martin den Heijer, Cees G M Kallenberg, Marc Bijl, Arnoud Loof, Wim B van den Berg, Leo A B Joosten, Vanessa Smith, Filip de Keyser, Rafaella Scorza, Claudio Lunardi, Piet L C M van Riel, Madelon Vonk, Waander van Heerde, Stephan Meller, Bernhard Homey, Lorenzo Beretta, Mark Roest, Maria Trojanowska, Robert Lafyatis, and Timothy R D J Radstake.
• The authors' affiliations are listed in the Appendix.
• N. Engl. J. Med.. 2014 Jan 30;370(5):433-43.

BackgroundPlasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon.MethodsWe 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.ResultsProteome-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.ConclusionsLevels 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.).

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