Immune-modulation by the placenta and its dysregulation in preeclampsia : role of syncytiotrophoblast microparticles and cytokines

The present study focuses on exploring the role of placental syncytiotrophoblast microparticles (STBM) during normal pregnancy and preeclampsia. In particular, the qualitative properties of the STBM were examined and the effects of STBM and placentally derived cytokines were studied on immune cells. Three STBM methods were used to generate qualitatively different STBM: A. Villous explant culture (vSTBM) B. Perfusion of a single placental cotyledon (pSTBM) These two methods were used for the first time. STBM were also prepared by third well established method: C. Mechanical dissection of the villous tissue (mSTBM) The qualitative assessment of the three STBM reveled that all the three STBM preparations are morphologically similar. But biochemically these three STBM preparations differ in the presence of syncytiotrophoblast protein PLAP, nucleic acids (DNA and RNA) and lipids. Functionally the three STBM behaved differently on endothelial cell cultures in that all the STBM preparations inhibited endothelial cell proliferation in different manner. Only mSTBM induced apoptosis in the endothelial cells further confirming that these three STBM preparations also differ biologically. Comparative study of the three STBM preparations and placentally derived cytokines on purified T cell response in terms of T cell activation, proliferation, cytokine production and apoptosis further confirmed that the three STBM preparations differ in their qualitative nature. These differences among three STBM preparations are attributable to their mode of preparation. Placentally derived cytokines and STBM mostly reduced T cell responses. These findings suggest that placental factors help in immune modulation, which is essentially required for successful pregnancy completion. The effects of the placentally derived factors were also examined on the innate immune response. For the first time we were able to show that placentally derived factors IL-8 and STBM were able to generate neutrophil extracellular traps (NETs). This is the first indication where physiological signals have been shown to generate NETs. Furthermore, massive presence of the neutrophil NETs were observed in the preeclamptic placenta, which might make a revolutionary change in our
understanding of the pathogenesis of this pregnancy related disorder.