Human placental villi immune cells help maintain homeostasis in utero

Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after T cell receptor (TCR) stimulation and when exposed to maternal uterine antigens. Finally, we report that cytokine production by PV T cells is sensitive to TCR stimulation and varies between mid-gestation, preterm (26-35 weeks) and term deliveries (37-40 weeks). Collectively, we elucidated the complexity and functional maturity of fetal immune cells within the PV and highlighted their immunosuppressive potential.

Evidence for HPV DNA in the placenta of women who resorted to elective abortion

Background It is believed that HPV infection can result in the death of placental trophoblasts and cause miscarriages or preterm birth. In clinical cases of placental villi positive for HPV DNA reported by other authors, contamination is suspected in the act of crossing the cervical canal. We analyzed placental samples of women who resorted to elective abortion obtained by hysterosuction of ovular material, bypassing any contact with the cervical canal and vagina. Methods We studied the chorionic villi of the placenta of 64 women who resorted to voluntary termination of pregnancy, in the first trimester. To avoid contamination of the villi by the cervical canal, we analyzed placental samples obtained by hysterosuction of ovular material, bypassing any contact with the cervical canal and vagina. All samples of chorionic villi were manually selected from the aborted material and subjected to research for HPV DNA. Results HPV DNA was detected in 10 out of 60 women (16.6%). The HPV DNA identified in the placenta belonged to genotypes 6, 16, 35, 53, and 90. Conclusion The study shows that papillomavirus DNA can infect the placenta and that placenta HPV infection can occur as early as the first trimester of pregnancy.

Expression of the Carbohydrate Lewis Antigen, Sialyl Lewis A, Sialyl Lewis X, Lewis X, and Lewis Y in the Placental Villi of Patients With Unexplained Miscarriages

BackgroundLewis antigens such as Sialyl Lewis A (sLeA), Sialyl Lewis X (sLeX), Lewis X (LeX), and Lewis Y (LeY) are a class of carbohydrate molecules that are known to mediate adhesion between tumor cells and endothelium by interacting with its selectin ligands. However, their potential role in miscarriage remains enigmatic. This study aims to analyze the expression pattern of sLeA, sLeX, LeX, and LeY in the placental villi tissue of patients with a medical history of unexplained miscarriages.MethodsParaffin-embedded slides originating from placental tissue were collected from patients experiencing a miscarriage early in their pregnancy (6–13 weeks). Tissues collected from spontaneous (n = 20) and recurrent (n = 15) miscarriages were analyzed using immunohistochemical and immunofluorescent staining. Specimens obtained from legally terminated normal pregnancies were considered as control group (n = 18). Assessment of villous vessel density was performed in another cohort (n = 10 each group) of gestation ages-paired placenta tissue. Protein expression was evaluated with Immunoreactive Score (IRS). Statistical analysis was performed by using Graphpad Prism 8.ResultsExpression of sLeA, sLeX, LeX, and LeY in the syncytiotrophoblast was significantly upregulated in the control group compared with spontaneous and recurrent miscarriage groups. However, no prominent differences between spontaneous and recurrent miscarriage groups were identified. Potential key modulators ST3GAL6 and NEU1 were found to be significantly downregulated in the recurrent miscarriage group and upregulated in the spontaneous group, respectively. Interestingly, LeX and LeY expression was also detected in the endothelial cells of villous vessels in the control group but no significant expression in miscarriage groups. Furthermore, assessment of villous vessel density using CD31 found significantly diminished vessels in all size groups of villi (small villi <200 µm, P = 0.0371; middle villi between 200 and 400 µm, P = 0.0010 and large villi >400 µm, P = 0.0003). Immunofluorescent double staining also indicated the co-localization of LeX/Y and CD31.ConclusionsThe expression of four mentioned carbohydrate Lewis antigens and their potential modulators, ST3GAL6 and NEU1, in the placenta of patients with miscarriages was significantly different from the normal pregnancy. For the first time, their expression pattern in the placenta was illustrated, which might shed light on a novel understanding of Lewis antigens’ role in the pathogenesis of miscarriages.

Induction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic Placenta

Preeclampsia is a hypertensive disorder of pregnancy that is a major cause of maternal-fetal morbidity and mortality worldwide. Severe preeclampsia (sPE) is mediated by pathology of the placental villi resulting in repressed PIGF (placental growth factor) production and hyper-secretion of sFLT1 (soluble fms-like tyrosine kinase 1), the net effect being wide-spread maternal endothelial dysfunction. Villous trophoblast differentiation is under control of the PPARγ (peroxisome proliferator-activated receptor γ) and GCM1 (glial cell missing 1) axis which is dysregulated in sPE. We hypothesized that disruption of trophoblast differentiation via the PPARγ-GCM1 axis is a major contribution to excess production of sFLT1 and pharmacological activation of PPARγ in the sPE placenta could reduce sFLT1 to normal levels. sPE, age-matched control placentas and first-trimester villous explants, were used to investigate the molecular relationships between PPARγ-GCM1 and sFLT1. We modulated this pathway by pharmacological activation/inhibition of PPARγ using Rosiglitazone and T0070907, respectively, and through siRNA repression of GCM1. PPARγ and GCM1 protein expressions are reduced in the sPE placenta while FLT1 protein and sFLT1 secretion are increased. GCM1 reduction in the first trimester explants significantly increased sFLT1 secretion, suggesting GCM1 as a key player in this pathway. Activation of PPARγ restored GCM1 and significantly reduced sFLT1 expression and release in first trimester and sPE placental villi. Functional integrity of the PPARγ-GCM1 axis in the villous trophoblast is critical for normal pregnancy development and is disrupted in the sPE placenta to favor excessive production of sFLT1. Pharmacological manipulation of PPARγ activity has the potential to rescue the antiangiogenic state of sPE and thereby prolong pregnancy and deliver improved clinical outcomes.