Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.
Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.
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DOI：
10.1056/nejmoa1114576
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发表时间：
2014-01-30
期刊：
影响因子：
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通讯作者：
Radstake TR
中科院分区：
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作者：
van Bon L;Affandi AJ;Broen J;Christmann RB;Marijnissen RJ;Stawski L;Farina GA;Stifano G;Mathes AL;Cossu M;York M;Collins C;Wenink M;Huijbens R;Hesselstrand R;Saxne T;DiMarzio M;Wuttge D;Agarwal SK;Reveille JD;Assassi S;Mayes M;Deng Y;Drenth JP;de Graaf J;den Heijer M;Kallenberg CG;Bijl M;Loof A;van den Berg WB;Joosten LA;Smith V;de Keyser F;Scorza R;Lunardi C;van Riel PL;Vonk M;van Heerde W;Meller S;Homey B;Beretta L;Roest M;Trojanowska M;Lafyatis R;Radstake TR
浆细胞样树突状细胞通过先前提出的产生I型干扰素以外的机制参与系统性硬化症的发病机制。我们从健康人和具有不同临床表型的系统性硬化症患者中分离出浆细胞样树突状细胞。然后，我们进行了蛋白质组分析，并在五个大型系统性硬化症患者队列中验证了这些观察结果。接下来，我们将结果与系统性红斑狼疮、强直性脊柱炎和肝纤维化患者的结果进行了比较。我们将CXCL 4蛋白的血浆水平与系统性硬化症的特征相关联，并研究了CXCL 4在体外和体内的直接作用。全蛋白质组分析和验证表明，CXCL 4是系统性硬化症中浆细胞样树突状细胞分泌的主要蛋白质，无论是在循环中还是在皮肤中。系统性硬化症患者CXCL 4的平均（±SD）水平为25，624 ±2652 pg/ml，显著高于对照组（92.5±77.9 pg/ml），高于系统性红斑狼疮患者（1346±1011 pg/ml）、强直性脊柱炎（1368±1162 pg/ml）或肝纤维化（1668±1263 pg/ml）。CXCL 4水平与皮肤和肺纤维化以及肺动脉高压相关。在趋化因子中，只有CXCL 4可以预测系统性硬化症的风险和进展。在体外，CXCL 4下调转录因子FLI 1的表达，诱导内皮细胞活化的标志物，并增强Toll样受体的反应。在体内，CXCL 4诱导炎症细胞的流入和皮肤转录组的变化，如在系统性硬化症。系统性硬化症患者的CXCL 4水平升高，并与并发症的存在和进展相关，如肺纤维化和肺动脉高压。（由荷兰关节炎协会和其他机构资助。
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 downregulated 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.)