Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome

Abstract

BackgroundPre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women.Methodsperipheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry.Resultscirculating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01).ConclusionsAberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.

Association between Plasma HLA-DR+ Placental Vesicles and Preeclampsia: A Pilot Longitudinal Cohort Study

“…Out of sixteen patients with HLA-DR-positive STEVs in the first trimester, six developed PE (38%), with a prevalence of STEV HLA-DR positivity in PE cases, consistent with previous observations [6,7]. A significant difference was found between the non-PE and PE groups in terms of HLA-DR positivity of STEVs during the first trimester of pregnancy (Figure 4a).…”

“…In a previous study, aberrant expression of the HLA-DR antigen was found in approximately 40% of STEVs obtained from PE women by double placenta perfusion and confirmed by immunohistochemistry on placental sections [6] A subsequent study from the same group demonstrated the abnormal expression of HLA-DR in serum STEVs in women with clinically overt PE (64%) during the third trimester of pregnancy. None of the normal pregnant women showed detectable positivity for HLA-DR in circulating STEVs [7].…”

Circulating extracellular vesicles in healthy and pathological pregnancies: A scoping review of methodology, rigour and results

“…Investigation of EV populations deriving from a specific cell type, via surface marker phenotyping, was performed in 58/152 studies. We reviewed the quantification data from 54 of these, as the remaining four presented data as fold‐change, % of EVs of specific cellular derivation, flow cytometric plots without numbers, or without absolute counts of particles (Pap et al., 2008; Tersigni et al., 2021; Walenta et al., 2012; Wong et al., 2015). The concentration of cell‐specific EVs in the blood of healthy non‐pregnant, healthy pregnant, or pathological pregnant participants, measured by either flow cytometry (FC) or fNTA, are summarised in Figure 8a.…”

Are there foetal extracellular vesicles in maternal blood? Prospects for diagnostic biomarker discovery

“…A number of studies have demonstrated PLAP+ EVs in maternal blood. PLAP is present both in small EVs of a size consistent with exosomes and microvesicles [83,84,86,89,90], and in larger SNAs [91][92][93][94][95][96].…”

“…Surface markers include general EV biomarkers such as CD63, as well as tissue-specific markers such as PLAP. Many studies have shown that placental-derived EVs are altered in diseases such as pre-eclampsia, gestational diabetes mellitus and intrauterine growth restrictions [86,89,90,[92][93][94][95], but it is more difficult to convincingly demonstrate changes in foetal-derived EVs in disease. Post-translational modifications such as glycosylation increase diversity of these markers.…”