Department of Medicine, Karolinska University Hospital, Huddinge and Karolinska Institutet, Stockholm, Sweden.
Scand J Rheumatol. 2010;39(1):77-83. doi: 10.3109/03009740903124432.
Anti-phospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), are risk factors for cardiovascular disease (CVD) in the general population and in patients with the anti-phospholipid syndrome (APS; Hughes syndrome). APS may be primary but is also common in patients with systemic lupus erythematosus (SLE). The anti-coagulant protein annexin A5 (ANXA5) is implicated in CVD by interfering with phospholipids and aPL.
ANXA5 binding to human umbilical venous endothelial cells (HUVECs) was determined by flow cytometry.
When cells were cultured in serum from APS patients with a high aPL titre (aPL-S), binding of ANXA5 to HUVECs was reduced. Monoclonal immunoglobulin (Ig)G aPL against cardiolipin (mAb-CL) dose-dependently reduced ANXA5 binding to endothelium. Preincubation of intravenous (IV)Ig at therapeutically relevant doses with aPL-S and mAb-aCL restored ANXA5 binding to comparable levels when normal healthy serum (NHS) was used. By contrast, IVIg per se had the capacity to reduce ANXA5 binding to endothelium when added to NHS (but not to aPL-S).
Decreased ANXA5 binding to endothelium, mediated by aPL, is a novel mechanism of atherothrombosis that can be countered by IVIg in vitro. IVIg per se could, to a lesser degree, cause decreased ANXA5 binding in NHS, which raises the possibility that some antibodies in IVIg can be involved in a side-effect reported in IVIg treatment, namely atherothrombosis and CVD. Increasing ANXA5 binding, either by addition of ANXA5 or by use of neutralizing antibodies in IVIg, represents a possible therapeutic strategy that deserves further study.
抗磷脂抗体（aPL），包括抗心磷脂抗体（aCL），是普通人群和抗磷脂综合征（APS；Hughes 综合征）患者心血管疾病（CVD）的危险因素。APS 可能是原发性的，但也常见于系统性红斑狼疮（SLE）患者。抗凝蛋白 annexin A5（ANXA5）通过干扰磷脂和 aPL 而与 CVD 有关。
通过流式细胞术测定 ANXA5 与人脐静脉内皮细胞（HUVEC）的结合。
当细胞在 APS 患者高 aPL 滴度（aPL-S）的血清中培养时，ANXA5 与 HUVEC 的结合减少。针对心磷脂的单克隆免疫球蛋白（Ig）G 抗体（mAb-CL）剂量依赖性地降低了 ANXA5 与内皮的结合。用 aPL-S 和 mAb-aCL 将治疗相关剂量的静脉内（IV）Ig 预先孵育，当使用正常健康血清（NHS）时，恢复了与 ANXA5 结合到可比水平。相比之下，IVIg 本身在添加到 NHS 时（而不是 aPL-S 时）就具有降低 ANXA5 与内皮结合的能力。
aPL 介导的 ANXA5 与内皮的结合减少是动脉血栓形成的一种新机制，在体外可被 IVIg 逆转。IVIg 本身在 NHS 中可能会在较小程度上引起 ANXA5 结合减少，这提示 IVIg 中的一些抗体可能与 IVIg 治疗中报告的一种副作用，即动脉血栓形成和 CVD 有关。增加 ANXA5 的结合，无论是通过添加 ANXA5 还是通过在 IVIg 中使用中和抗体，都代表了一种值得进一步研究的可能的治疗策略。
