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

L. van Bon; A.J. Affandi; J.C.A. dr. Broen; R.B. Christmann; R.J. Marijnissen; L. Stawski; G.A. Farina; G. Stifano; A.L. Mathes; M. Cossu; M. York; C. Collins; M.H. Wenink; R. Huijbens; R. Hesselstrand; T. Saxne; M Dimarzio; D. Wuttge; S.K. Agarwal; J.D. Reveille; S. Assassi; M.D. Mayes; Y. Deng; J.P. Drenth; J. de Graaf; M. den Heijer; C.G. Kallenberg; M. Bijl; A. de Loof; W.B. van der Berg; L.A. Joosten; V. Smith; F. de Keyser; R. Scorza; C. Lunardi; P.L.C.M. van Riel; M. Vonk; W.L. van Heerde; S. Meller; B. Homey; L. Beretta; M. Roest; M. Trojanowska; R. Lafyatis; T.R.D.J. Radstake

doi:10.1056/NEJMoa1114576

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

L. van Bon, A.J. Affandi, J.C.A. dr. Broen, R.B. Christmann, R.J. Marijnissen, L. Stawski, G.A. Farina, G. Stifano, A.L. Mathes, M. Cossu, M. York, C. Collins, M.H. Wenink, R. Huijbens, R. Hesselstrand, T. Saxne, M Dimarzio, D. Wuttge, S.K. Agarwal, J.D. ReveilleS. Assassi, M.D. Mayes, Y. Deng, J.P. Drenth, J. de Graaf, M. den Heijer, C.G. Kallenberg, M. Bijl, A. de Loof, W.B. van der Berg, L.A. Joosten, V. Smith, F. de Keyser, R. Scorza, C. Lunardi, P.L.C.M. van Riel, M. Vonk, W.L. van Heerde, S. Meller, B. Homey, L. Beretta, M. Roest, M. Trojanowska, R. Lafyatis, T.R.D.J. Radstake

Research output: Contribution to journal › Article › Academic › peer-review

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.).

Original language	English
Pages (from-to)	433-443
Number of pages	11
Journal	New England Journal of Medicine
Volume	370
Issue number	5
DOIs	https://doi.org/10.1056/NEJMoa1114576 https://doi.org/10.1056/NEJMoa1114576
Publication status	Published - 30 Jan 2014

Keywords

Adult
Animals
Biomarkers
Cytokines
Dendritic Cells
Familial Primary Pulmonary Hypertension
Female
Humans
Hypertension, Pulmonary
Male
Mice
Mice, Inbred C57BL
Middle Aged
Platelet Factor 4
Proteome
Pulmonary Fibrosis
RNA, Messenger
Scleroderma, Systemic
Skin
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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http://www.ncbi.nlm.nih.gov/pubmed/24350901

Cite this

van Bon, L., Affandi, A. J., dr. Broen, J. C. A., Christmann, R. B., Marijnissen, R. J., Stawski, L., Farina, G. A., Stifano, G., Mathes, A. L., Cossu, M., York, M., Collins, C., Wenink, M. H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M., Wuttge, D., Agarwal, S. K., ... Radstake, T. R. D. J. (2014). Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. New England Journal of Medicine, 370(5), 433-443. https://doi.org/10.1056/NEJMoa1114576, https://doi.org/10.1056/NEJMoa1114576

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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.).",

keywords = "Adult, Animals, Biomarkers, Cytokines, Dendritic Cells, Familial Primary Pulmonary Hypertension, Female, Humans, Hypertension, Pulmonary, Male, Mice, Mice, Inbred C57BL, Middle Aged, Platelet Factor 4, Proteome, Pulmonary Fibrosis, RNA, Messenger, Scleroderma, Systemic, Skin, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "{van Bon}, L. and A.J. Affandi and {dr. Broen}, J.C.A. and R.B. Christmann and R.J. Marijnissen and L. Stawski and G.A. Farina and G. Stifano and A.L. Mathes and M. Cossu and M. York and C. Collins and M.H. Wenink and R. Huijbens and R. Hesselstrand and T. Saxne and M Dimarzio and D. Wuttge and S.K. Agarwal and J.D. Reveille and S. Assassi and M.D. Mayes and Y. Deng and J.P. Drenth and {de Graaf}, J. and {den Heijer}, M. and C.G. Kallenberg and M. Bijl and {de Loof}, A. and {van der Berg}, W.B. and L.A. Joosten and V. Smith and {de Keyser}, F. and R. Scorza and C. Lunardi and {van Riel}, P.L.C.M. and M. Vonk and {van Heerde}, W.L. and S. Meller and B. Homey and L. Beretta and M. Roest and M. Trojanowska and R. Lafyatis and T.R.D.J. Radstake",

year = "2014",

month = jan,

day = "30",

doi = "10.1056/NEJMoa1114576",

language = "English",

volume = "370",

pages = "433--443",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "5",

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van Bon, L, Affandi, AJ, dr. Broen, JCA, Christmann, RB, Marijnissen, RJ, Stawski, L, Farina, GA, Stifano, G, Mathes, AL, Cossu, M, York, M, Collins, C, Wenink, MH, Huijbens, R, Hesselstrand, R, Saxne, T, Dimarzio, M, Wuttge, D, Agarwal, SK, Reveille, JD, Assassi, S, Mayes, MD, Deng, Y, Drenth, JP, de Graaf, J, den Heijer, M, Kallenberg, CG, Bijl, M, de Loof, A, van der Berg, WB, Joosten, LA, Smith, V, de Keyser, F, Scorza, R, Lunardi, C, van Riel, PLCM, Vonk, M, van Heerde, WL, Meller, S, Homey, B, Beretta, L, Roest, M, Trojanowska, M, Lafyatis, R & Radstake, TRDJ 2014, 'Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis', New England Journal of Medicine, vol. 370, no. 5, pp. 433-443. https://doi.org/10.1056/NEJMoa1114576, https://doi.org/10.1056/NEJMoa1114576

TY - JOUR

T1 - Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis

AU - van Bon, L.

AU - Affandi, A.J.

AU - dr. Broen, J.C.A.

AU - Christmann, R.B.

AU - Marijnissen, R.J.

AU - Stawski, L.

AU - Farina, G.A.

AU - Stifano, G.

AU - Mathes, A.L.

AU - Cossu, M.

AU - York, M.

AU - Collins, C.

AU - Wenink, M.H.

AU - Huijbens, R.

AU - Hesselstrand, R.

AU - Saxne, T.

AU - Dimarzio, M

AU - Wuttge, D.

AU - Agarwal, S.K.

AU - Reveille, J.D.

AU - Assassi, S.

AU - Mayes, M.D.

AU - Deng, Y.

AU - Drenth, J.P.

AU - de Graaf, J.

AU - den Heijer, M.

AU - Kallenberg, C.G.

AU - Bijl, M.

AU - de Loof, A.

AU - van der Berg, W.B.

AU - Joosten, L.A.

AU - Smith, V.

AU - de Keyser, F.

AU - Scorza, R.

AU - Lunardi, C.

AU - van Riel, P.L.C.M.

AU - Vonk, M.

AU - van Heerde, W.L.

AU - Meller, S.

AU - Homey, B.

AU - Beretta, L.

AU - Roest, M.

AU - Trojanowska, M.

AU - Lafyatis, R.

AU - Radstake, T.R.D.J.

PY - 2014/1/30

Y1 - 2014/1/30

N2 - 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.).

AB - 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.).

KW - Adult

KW - Animals

KW - Biomarkers

KW - Cytokines

KW - Dendritic Cells

KW - Familial Primary Pulmonary Hypertension

KW - Female

KW - Humans

KW - Hypertension, Pulmonary

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Platelet Factor 4

KW - Proteome

KW - Pulmonary Fibrosis

KW - RNA, Messenger

KW - Scleroderma, Systemic

KW - Skin

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1114576

DO - 10.1056/NEJMoa1114576

M3 - Article

C2 - 24350901

SN - 0028-4793

VL - 370

SP - 433

EP - 443

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 5

ER -

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

Abstract

Keywords

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