Objective

Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by recurrent thrombosis and/or pregnancy morbidity, in the presence of antibodies to β2 glycoprotein-I (β2GPI), prothrombin or Lupus anticoagulant (LA). Anti-β2GPI antibodies recognize complexes of β2GPI dimers with CXCL4 chemokine and activate platelets. Thrombospondin 1 (TSP-1) is secreted by platelets and exhibits prothrombotic and proinflammatory properties. Therefore, we investigated its implication in APS.

Methods

Plasma from APS patients (n = 100), Systemic Lupus Erythematosus (SLE) (n = 27) and healthy donors (HD) (n = 50) was analyzed for TSP-1, IL-1β, IL-17A and free active TGF-β1 by ELISA. Human Umbilical Vein Endothelial Cells (HUVECs) and HD monocytes were treated with total HD-IgG or anti-β2GPI, β2GPI and CXCL4 and CD4⁺ T-cells were stimulated by monocyte supernatants. TSP-1, IL-1β, IL-17A TGF-β1 levels were quantified by ELISA and Real-Time PCR.

Results

Higher plasma levels of TSP-1 and TGF-β1, which positively correlated each other, were observed in APS but not HDs or SLE patients. Patients with arterial thrombotic events or those undergoing a clinical event had the highest TSP-1 levels. These patients also had detectable IL-1β, IL-17A in their plasma. HD-derived monocytes and HUVECs stimulated with anti-β2GPI-IgG-β2GPI-CXCL4 secreted the highest TSP-1 and IL-1β levels. Supernatants from anti-β2GPI-β2GPI-CXCL4 treated monocytes induced IL-17A expression from CD4⁺ T-cells. Transcript levels followed a similar pattern.

Conclusions

TSP-1 is probably implicated in the pathogenesis of APS. In vitro cell treatments along with high TSP-1 levels in plasma of APS patients suggest that high TSP-1 levels could mark a prothrombotic state and an underlying inflammatory process.

中文翻译：

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血小板反应蛋白-1在抗磷脂综合征发病机制中的作用。

客观的

抗磷脂综合征 (APS) 是一种获得性血栓形成倾向，其特征是反复血栓形成和/或妊娠发病率，存在针对 β2 糖蛋白-I (β2GPI)、凝血酶原或狼疮抗凝剂 (LA) 的抗体。抗 β2GPI 抗体识别 β2GPI 二聚体与 CXCL4 趋化因子的复合物并激活血小板。血小板反应蛋白 1 (TSP-1) 由血小板分泌，具有促血栓形成和促炎特性。因此，我们研究了它在 APS 中的含义。

方法

分析了来自 APS 患者（n = 100）、系统性红斑狼疮（SLE）（n = 27）和健康供体（HD）（n = 50）的血浆中的 TSP-1、IL-1β、IL-17A 和游离活性 TGF -β1 通过 ELISA。人脐静脉内皮细胞 (HUVEC) 和 HD 单核细胞用总 HD-IgG 或抗-β2GPI、β2GPI 和 CXCL4 处理，CD4 ⁺ T 细胞由单核细胞上清液刺激。通过ELISA和实时PCR定量TSP-1、IL-1β、IL-17A TGF-β1水平。

结果

在 APS 而非 HD 或 SLE 患者中观察到较高的 TSP-1 和 TGF-β1 血浆水平，它们彼此呈正相关。发生动脉血栓事件或发生临床事件的患者的 TSP-1 水平最高。这些患者的血浆中也可检测到 IL-1β、IL-17A。用抗-β2GPI-IgG-β2GPI-CXCL4刺激的 HD 衍生单核细胞和 HUVEC分泌最高的 TSP-1 和 IL-1β 水平。来自抗-β2GPI-β2GPI-CXCL4 处理的单核细胞的上清液诱导了来自 CD4 ⁺ T 细胞的IL-17A 表达。转录水平遵循类似的模式。

结论

TSP-1 可能与 APS 的发病机制有关。体外细胞治疗以及 APS 患者血浆中的高 TSP-1 水平表明，高 TSP-1 水平可能标志着血栓前状态和潜在的炎症过程。