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Effects of anti-cardiolipin antibodies and IVIg on annexin A5 binding to endothelial cells: implications for cardiovascular disease

Objectives: 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. Methods: ANXA5 binding to human umbilical venous endothelial cells (HUVECs) was determined by flow cytometry. Results: 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). Conclusions: 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.