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Problem: T-cells are key players in fighting the coronavirus disease 2019 (COVID-19). The checkpoint molecule B7-H4, a member of the B7 family, can inhibit T-cell activation and proliferation by inhibiting NF-kb expression. We aimed to elucidate the immunological role of soluble B7-H4 (sB7-H4) and B7-H4 in pregnant women suffered from an acute Sars-Cov2 infection. Methods: Expression levels of sB7-H4 and cytokines were detected by enzyme linked immunosorbent assay. B7-H4 and cytokines mRNA expression was analyzed by qPCR, and B7-H4 and NF-κb (p65) protein levels were investigated by western blot and immunofluorescence staining in placenta chorionic villous and decidual basalis tissues of COVID-19 affected women and healthy controls. Results: Fibrinoid necrosis in the periphery of placental villi was increased in the COVID-19-affected patients. sB7-H4 protein in maternal and cord blood serum and IL-6/IL-10 were increased while leukocytes were decreased during SARS-CoV-2 infection. Serum sB7-H4 level was increased according to the severity of SARS-Cov-2 infection. Cytokines (IL-6, IL-18, IL-1β, TNF-α), B7-H4 mRNA and protein in the decidual basalis tissues of COVID-19-infected pregnant women were significantly increased compared to healthy controls. IL-18 and IL-1β were significantly increased in the placenta chorionic villous samples of COVID-19 affected patients, while NF-κb (p65) expression was decreased. Conclusions: The expression of the immunological marker sB7-H4 correlated with the severity of COVID-19 disease in pregnant women. sB7-H4 and B7-H4 can be used to monitor the progression of COVID-19 infection during pregnancy, and for evaluating of the maternal immune status.

BackgroundThe sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio serves as a clinical biomarker to predict the hypertensive, placenta-derived pregnancy disorder pre-eclampsia which is often associated with placental dysfunction and fetal growth restriction. Additionally elevated levels also indicate an increased risk for prematurity. However, its predictive value for subsequent neonatal neurological outcome has not been studied.ObjectiveThis study aimed to evaluate the correlation of maternal sFlt-1/PlGF ratio with early motor outcome of preterm infants. Design/Methods: 88 preterm infants (gestational age ≤ 34 + 0) born between February 2017 and August 2020 at the Department of Obstetrics and Gynecology, University Hospital Essen in Germany, were included, when the following variables were available: maternal sFlt-1/PlGF levels at parturition and general movement assessment of the infant at the corrected age of 3 to 5 months. The infants were stratified into high and low ratio groups according to maternal sFlt-1/PlGF cut-off values of 85. To investigate the early motor repertoire and quality of spontaneous movements of the infant, the Motor Optimality Score (MOS-R) based on antigravity movements and posture patterns, was applied. In the given age, special attention was paid to the presence of fidgety movements. Linear regressions were run to test differences in infants motor repertoire according to the maternal sFlt-1/PIGF ratio.ResultsLinear regression analysis showed that the sFlt-1/PlGF ratio does not predict the MOS-R score (β=≤0.001; p=0.282). However, children with birth weight below the 10th percentile scored significantly lower (mean 20.7 vs 22.7; p=0.035). These children were 91% in the group with an increased ratio, which in turn is a known predictor of low birth weight (β= -0.315; p <0.001). In the group with a high sFlt-1/PLGF ratio above 85 the mothers of female infants had a lower average sFlt-1/PlGF ratio compared to a male infant (median: 438 in female vs. 603 in male infant, p=0.145).ConclusionsIn our cohort, especially low birth weight, which correlated with an elevated sFlt-1/PlGF ratio, had a negative effect on the outcome in the MOS-R. A direct correlation between an increased ratio and a worse motor outcome was not demonstrated.

Problem: The aim of this study was to evaluate the soluble programmed death-ligand (sPD-L1) and soluble B7-H4 (sB7-H4) serum concentration levels longitudinal throughout the three trimesters of uncomplicated pregnancies. Method of the study: sPD-L1 and sB7-H4 levels were determined with enzyme-linked immunosorbent assay (ELISA). The patients (n = 26) were divided into three groups according to the pregnancy trimester. Among 26 women involved in the study 14 had longitudinal sB7-H4 and sPD-L1 measurements in each trimester of pregnancy. Results: During the course of pregnancy, the sB7-H4 blood serum levels were significant higher in second trimester than in first and third trimester, whereas sPD-L1 levels increased significantly over the course of pregnancy. Conclusion: The highest serum levels of sPD-L1 in the third trimester suggest increasing suppression of maternal immunity throughout pregnancy, whereas elevated sB7-H4 concentration levels in second trimester suggests different profile of T-cell regulation in physiological pregnancy.

Background B7-H4, a checkpoint molecule of the B7 family, regulates a broad spectrum such as T-cell activation, cytokine secretion, tumour progression and invasion capacities. Our previous data revealed that soluble B7-H4 (sB7-H4) blood serum levels are elevated in women at high risk for the hypertensive pregnancy disorder preeclampsia (PE) in the first trimester, as well as in patients with confirmed early/ late-onset PE. Aim We here aim to investigate the expression pattern of B7-H4 in placental tissues of PE and HELLP Syndrome versus control group. Methods B7-H4 protein expression and localization were investigated by immunoblotting as well as co-immunohistochemistry in placental chorionic villous and decidual basalis tissues. Results B7-H4 protein was prominently expressed at the cell membrane, in the cytoplasm of the syncytiotrophoblast (STB) and interstitial extravillous trophoblast (EVT). B7-H4 protein levels in placental chorionic villous tissue was significantly higher in women with early-onset/late-onset PE and HELLP, while it was decreased in decidual basalis tissues of early-onset PE and HELLP compared to controls. Conclusion B7-H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase of B7-H4 in the STB in PE and HELLP may lead to excessive apical expression and release of soluble B7-H4 in the maternal circulation. In contrast, the decrease of B7-H4 in decidual basalis tissues could be related to the decrease in invasion ability of the EVT in PE. Thus, the current results strongly suggest that B7-H4 is involved in the pathogenesis of PE and HELLP.