title: Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.
abstract: 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 (±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.
  
  
  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. (Funded by the Dutch Arthritis Association and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Lenny
authors.initials: L
authors.lastname: van Bon
authors.forename: Alsya J
authors.initials: AJ
authors.lastname: Affandi
authors.forename: Jasper
authors.initials: J
authors.lastname: Broen
authors.forename: Romy B
authors.initials: RB
authors.lastname: Christmann
authors.forename: Renoud J
authors.initials: RJ
authors.lastname: Marijnissen
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stawski
authors.forename: Giuseppina A
authors.initials: GA
authors.lastname: Farina
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Stifano
authors.forename: Allison L
authors.initials: AL
authors.lastname: Mathes
authors.forename: Marta
authors.initials: M
authors.lastname: Cossu
authors.forename: Michael
authors.initials: M
authors.lastname: York
authors.forename: Cindy
authors.initials: C
authors.lastname: Collins
authors.forename: Mark
authors.initials: M
authors.lastname: Wenink
authors.forename: Richard
authors.initials: R
authors.lastname: Huijbens
authors.forename: Roger
authors.initials: R
authors.lastname: Hesselstrand
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.forename: Mike
authors.initials: M
authors.lastname: DiMarzio
authors.forename: Dirk
authors.initials: D
authors.lastname: Wuttge
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Maureen
authors.initials: M
authors.lastname: Mayes
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Deng
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Marc
authors.initials: M
authors.lastname: Bijl
authors.forename: Arnoud
authors.initials: A
authors.lastname: Loof
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Vanessa
authors.initials: V
authors.lastname: Smith
authors.forename: Filip
authors.initials: F
authors.lastname: de Keyser
authors.forename: Rafaella
authors.initials: R
authors.lastname: Scorza
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Madelon
authors.initials: M
authors.lastname: Vonk
authors.forename: Waander
authors.initials: W
authors.lastname: van Heerde
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
authors.forename: Mark
authors.initials: M
authors.lastname: Roest
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010978:Platelet Factor 4 / Q000097:blood* / Q000378:metabolism; D020543:Proteome; D011658:Pulmonary Fibrosis / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000097:blood* / Q000209:etiology; D012867:Skin / Q000473:pathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020543:Proteome; D012333:RNA, Messenger; D010978:Platelet Factor 4