Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome.
Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome.
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DOI：
10.1136/annrheumdis-2016-209442
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发表时间：
2017-02
影响因子：
27.4
通讯作者：
Knight JS
中科院分区：
文献类型：
--
作者：
Grenn RC;Yalavarthi S;Gandhi AA;Kazzaz NM;Núñez-Álvarez C;Hernández-Ramírez D;Cabral AR;McCune WJ;Bockenstedt PL;Knight JS
抗磷脂综合征（APS）患者存在亚临床内皮损伤以及加速动脉粥样硬化的风险。在相关疾病系统性红斑狼疮中，循环内皮祖细胞存在公认的缺陷，这导致内皮损伤随着时间的推移而增加。这种缺陷至少部分归因于I型干扰素（IFN）的过度表达。我们试图确定这些途径在APS中是否重要。我们研究了68例原发性APS患者。通过流式细胞术和功能测定来评估内皮祖细胞。I型IFN活性通过公认的生物测定法测定，而外周血单核细胞（PBMC）的IFN应答基因的表达进行评分。来自APS患者的内皮祖细胞表现出分化成内皮细胞的能力的显著缺陷，这是一种可以通过用APS血清处理对照祖细胞来模拟的表型。在APS患者的循环中检测到I型IFN活性升高（随后在独立队列中复制了这一发现）。虽然APS血清中的IgG消耗并不能挽救内皮祖细胞功能，但I型IFN受体中和抗体成功逆转了这种功能障碍。我们描述了，第一次我们的知识，在原发性APS的IFN签名，并表明，这促进受损的内皮祖细胞功能。这项工作为可能减轻APS中血管损伤的新方法（如抗IFN药物）打开了大门。
Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells (PBMCs) were scored for expression of IFN-responsive genes. Endothelial progenitors from APS patients demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of APS patients (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralizing antibody. We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.