Cell-free nucleic acids in (maternal) blood: any relevance to (reproductive) immunologists?

Cell-free foetal DNA recently hit the international headlines by facilitating the non-invasive prenatal testing (NIPT) of foetal chromosomal anomalies directly from maternal blood samples. Being largely of placental origin, cell-free foetal DNA may also, however, provide insight into underlying pathological changes in preeclampsia, or the influences of external stresses, such as hypoxia. This analysis may be enhanced by the simultaneous assessment of placenta-derived, cell-free mRNA species. The source of maternal cell-free DNA is not readily apparent, but may involve neutrophil extracellular traps (NETs). The rapid rise in this material following removal of the placenta, especially in preeclampsia, may indicate a rapid transient maternal inflammatory response to placenta-derived debris. Since NETs have recently been shown to promote coagulation, this may provide a link to pregnancy-associated thrombosis or placental infarction. The presence of cell-free, placenta-derived DNA may not be as innocuous as commonly assumed, as it is largely hypomethylated and could, like bacterial DNA, trigger the activation of maternal immune effector cells via interaction with toll-like receptor 9 (TLR9), thereby contributing to an excessive inflammatory response in preeclampsia or preterm labour. Possibly the most fascinating aspect concerning placenta-derived, cell-free nucleic acids is the recent report that placental exosomes loaded with placenta-specific C19MC miRNA species may modulate the antiviral response of maternal immune cells, thereby ensuring foetal well-being.