E-Selectin mediates pathogenic effects of antiphospholipid antibodies

Abstract

Summary. Antiphospholipid (aPL) antibodies, detected in patients with antiphospholipid syndrome (APS) are associated with thrombosis, pregnancy loss and thrombocytopenia. Studies have shown that aPL are thrombogenic in vivo, but the mechanism(s) involved are not completely understood. Several studies have demonstrated that aPL antibodies activate endothelial cells (ECs) in vitro, as determined by up-regulation of adhesion molecules: E-selectin (E-sel); intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and in vivo. The objectives of these study were to determine the effects of aPL antibodies on the expression of E-selectin on ECs, on the adhesion of monocytes to ECs and to study the role of E-selectin on aPL antibodies enhanced thrombus formation and activation of ECs in vivo. We demonstrated that the surface expression of E-selectin on HUVEC by ELISA was increased 400-fold when treated with tumor necrosis factor-alpha (TNF-a) and 421-fold when treated with aPL antibodies during 4 h. APL antibodies also induced activation of the nuclear factorkappa B (NF-kB). APL antibodies increased signi®cantly the number of adhering leukocytes to ECs in vivo in C57BL/ 6 J mice when compared to IgG-NHS treated mice. This effect was abrogated in E-selectin-de®cient mice. The thrombus size was signi®cantly increased in C57BL/6 J mice treated with aPL antibodies when compared to mice treated with IgG-NHS. This enhancement in thrombus size by aPL antibodies was abrogated in E-selectin-de®cient mice treated with aPL antibodies.

Receptors involved in cell activation by antiphospholipid antibodies

“…Immunization of mice with β2GP1 or injection of human aPLA in mice increased thrombus size in murine thrombosis models and induced recurrent pregnancy loss. Thrombus formation was significantly reduced or abrogated in mice lacking the leukocyte adhesion molecules ICAM-1, E-selectin or P-selectin or by injection with anti-VCAM-1 antibodies [12,13]. These results imply that activation of the vascular endothelium by aPLA is a major thrombogenic mechanism [14].…”

Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state

“…Once endothelial cells become activated, up-regulation of TF may be further augmented by a synergistic effect of TNF-a and factor Xa [37]. Other changes typical for this prothrombotic phenotype include increased expression of adhesion molecules (ICAM-1, VCAM-1, selectins E and P) [38,39], and formation of endothelial microparticles [40]. Raschi et al have shown that anti-beta 2 GPI antibodies induce translocation of NFjB in a manner similar to that elicited by LPS and TNF-a.…”

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

“…Studies have shown conclusively that aPL are thrombogenic in in vivo animal models (23)(24)(25). The prothrombotic properties of aPL may be explained in part by their ability to enhance the activation of platelets.…”