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 and 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 were 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 with controls. Conclusion B7‐H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase in 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 in 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.

Objectives An adequate development of the placenta includes trophoblast differentiation with the processes of trophoblast migration, invasion, cellular senescence and apoptosis which are all crucial to establishing a successful pregnancy. Altered placental development and function lead to placental diseases such as preeclampsia (PE) which is mainly characterized by insufficient trophoblast invasion and abnormally invasive placenta (AIP) disorders ( Placenta accreta , increta , or percreta) which are characterized by excessive trophoblast invasion. Both of them will cause maternal and fetal morbidity/mortality. However, the etiology of these diseases is still unclear. Our previous study has shown that the matricellular protein nephroblastoma overexpressed (NOV, CCN3) induces G0/G1 cell cycle arrest, drives trophoblast cells into senescence and activates FAK and Akt kinases resulting in reduced cell proliferation and enhanced migration capability of the human trophoblast cell line SGHPL-5. The present study focuses on whether CCN3 can alter cell cycle-regulated pathways associated with trophoblast senescence and invasion activity in pathological versus gestational age-matched control placentas. Methods Cell cycle regulator proteins were investigated by immunoblotting and qPCR. For localization of CCN3, p16, p21, and Cyclin D1 proteins, co-immunohistochemistry was performed. Results In early-onset PE placentas, CCN3 was expressed at a significantly lower level compared to gestational age-matched controls. The decrease of CCN3 level is associated with an increase in p53, Cyclin E1 and pRb protein expression, whereas the level of cleaved Notch-1, p21, Cyclin D1, pFAK, pAKT, and pmTOR protein decreased. In term AIP placentas, the expression of CCN3 was significantly increased compared to matched term controls. This increase was correlated to an increase in p53, p16, p21, Cyclin D1, cleaved Notch-1, pFAK, pAkt, and pmTOR whereas pRb was significantly decreased. However, in late PE and early AIP placentas, no significant differences in CCN3, p16, p21, Cyclin D1, p53, and cleaved Notch-1 expression were found when matched to appropriate controls. Conclusions CCN3 expression levels are correlated to markers of cell cycle arrest oppositely in PE and AIP by activating the FAK/AKT pathway in AIP or down-regulating in PE. This may be one mechanism to explain the different pathological features of placental diseases, PE and AIP.

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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.

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