Trophoblast deportation: just a waste disposal system or antigen sharing?

Trophoblast deportation, the removal of trophoblastic debris from the placenta via the maternal blood, was first described over 100 years ago. Deported trophoblastic debris ranges in size from nano-meter scale subcellular particles to large multinucleated syncytial knots. Whether trophoblast deportation has any biological significance remains unclear. However, the (semi) allogeneic fetus must induce maternal tolerance to paternally inherited placental antigens. We propose that the clearance of deported trophoblasts may be a mechanism by which the maternal immune system is maintained in a state of tolerance towards paternal antigens. Using an in vitro model, we have shown that when syncytial knots are shed by an apoptosis-like programmed cell death process, then phagocytosed by macrophages, the macrophages produce a tolerogenic response. However, necrotic syncytial knots, when phagocytosed, appear to be immunostimulatory. We have also shown that endothelial cells are likely to be involved in the clearance of syncytial knots from the pulmonary vessels. Phagocytosis of apoptotic syncytial knots by endothelial cells is silent while phagocytosis of necrotic syncytial knots leads to endothelial cell activation characterised by increased endothelial cell-surface adhesion molecule expression and secretion of IL-6 and TGFβ1. All of these molecules may interact with the maternal immune system to exacerbate any adverse maternal response. We propose that in normal pregnancy clearance of apoptotic syncytial knots is important to maintain maternal immune tolerance to the fetus and that in abnormal pregnancies, especially preeclampsia, clearance of necrotic syncytial knots may contribute to the pathogenesis of that condition.