Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome.

Abstract

The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor beta2-glycoprotein I (beta2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-beta2GPI antibodies obtained from one patient possess pathogenic properties. Three beta2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind beta2GPI immobilized on irradiated plates, yet only ILA-1 bound beta2GPI coated onto nonirradiated plates. Furthermore, when using the anti-beta2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase beta2GPI. ILA-1 and ILA-3, but not ILA-4, induced adherence of U937 cells to endothelial cells in vitro (reflecting activation of endothelial cells). mAbs ILA-1 and ILA-3 as opposed to ILA-4 induced significant expression of adhesion molecules when preincubated with human umbilical vein endothelial cells. Passive administration of ILA-1 and ILA-3 to pregnant BALB/c mice induced clinical findings consistent with APS (increased fetal resorptions, reduced platelet counts, and prolonged activated partial thromboplastin time), whereas both ILA-4 and the control human IgM did not produce similar effects. The results of the study demonstrate the differential effects of various populations of anti-beta2GPI antibodies on endothelial cell activation and on experimental APS.