Quantitative and qualitative rapid immune cell activation profiling to allow identification and follow up of at-risk neonates admitted to ICU

Preeclampsia, a placentally-driven disease, is a leading cause of morbidity and mortality in the perinatal space and is responsible for 75,000 maternal and 500,000 neonatal deaths every year. The disease causes hypertension, endothelial disruption and widespread immune dysfunction. However, there is currently no standardized method for determining who will develop preeclampsia, or how severe it will be. This Medical Research Council iCASE (industrial collaborative award in science and engineering) doctoral studentship, in partnership with Sysmex, hopes to solve this issue through analysis of the pathophysiology of preeclampsia and its clinical sequelae. The syncytiotrophoblast is the layer of the placenta in direct contact with the uterus and releases extracellular vesicles (STBEVs) in normal pregnancy. STBEVs are much more abundant in PE and have been shown to contribute significantly to the pathogenesis of preeclampsia, for example in clotting and immune function. Several biomarkers have already been identified which allow for the distinction of STBEVs from normal and preeclamptic placentas. The Sysmex Exocounter has been validated for quantification and detection of STBEVs with disease characteristics in plasma samples. Furthermore, there is no definition of the immune cell activation status for individuals with preeclampsia or other adverse pregnancy outcomes. Current diagnostic tools utilizing white cells counts and CRP are suboptimal because pregnancy, especially the process of labour, is highly inflammatory and thus such parameters may be elevated in the absence of adverse pregnancy outcomes. Women undergo routine clinical blood tests throughout pregnancy, which are routinely analysed at using the Sysmex XN analyser. Only a few parameters (e.g., white cell count and CRP) are reported to clinicians, although the analysers also measure several other parameters, which are not routinely reported.
The aims of this project are as follows:
1. Quantify circulating STBEVs (normal and preeclampsia/adverse outcomes) carrying a unique marker (placental alkaline-phosphatase) using the Sysmex Exocounter.
2. Characterize the immune cell activation status in normal women (those with no clinical or haematological suspicion of preeclampsia or other adverse pregnancy outcomes), and in women with confirmed preeclampsia/adverse outcomes.
3. Explore the effects of STBEVs (normal and preeclampsia/adverse outcomes) on haematological, immune and endothelial cell lines using proteomic, transcriptomic and advanced imaging data.
4. Integrate the data from Aims 1-3 to identify potential pathways implicated in preeclampsia and other adverse pregnancy outcomes in order to create biological/clinical evidence for any changes in immune cell activation status seen in Aim 2.
5. Utilise the combined international networks of NDWRH and Sysmex to establish a worldwide patient validation cohort to ensure the findings of Aim 2 are globally translatable.