Anti-phospholipid antibodies increase non-apoptotic trophoblast shedding: a contribution to the pathogenesis of pre-eclampsia in affected women?

Pre-eclampsia is associated with trophoblast shedding-deportation and endothelial cell dysfunction. Anti-phospholipid autoantibodies increase a women's risk factor of developing pre-eclampsia. In this study we examined the hypothesis that anti-phospholipid antibodies alter the number and nature of trophoblasts shed from the placenta, and that phagocytosis of these altered trophoblasts results in endothelial cell activation. To investigate this we used a placental explant model in which explants were treated with anti-phospholipid antibodies. This treatment resulted in a doubling of the amount of trophoblast shed from the explants. Furthermore, the trophoblasts shed from anti-phospholipid antibody-treated explants were more readily phagocytosed by endothelial cells and subsequently caused the activation of the endothelial cells, as indicated by increased expression of endothelial cell surface ICAM-1 determined by cell-based ELISA, and monocyte adhesion as determined by flow cytometry. Confocal microscopy analysis of trophoblasts shed from anti-phospholipid antibody-treated or control explants demonstrated that anti-phospholipid antibodies, but not control antibodies, were internalised within trophoblasts shed from the explants, and this was accompanied by a reduction in the activity of caspases 3 and 7 in the shed trophoblasts as indicated by FLICA. These results suggest that anti-phospholipid antibodies are selectively transported into trophoblasts where they affect the regulation of the cell cycle leading to excess and aberrant death (necrotic or aponecrotic) and shedding of trophoblasts. If reflected in vivo this might explain, at least in part, how anti-phospholipid antibodies contribute to the pathogenesis of pre-eclampsia.