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At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, uncertainties about the virus and its dangers during pregnancy caused great uncertainty and fear, especially among pregnant women. New data suggest an increased risk of obstetric complications, including maternal complications, preterm labor, intrauterine growth restriction, hypertensive disorders, stillbirths, gestational diabetes and risk, of neonatal developmental disorders. In addition, preeclampsia (PE)-like syndromes were also induced by severe COVID-19 infection. Therefore, the aim of this study was to investigate the expression of CD68 and CD163 and PD-L1 on placental tissues from acute covid patients, patients who survived a covid-19 infection and normal term controls that are known to be dysregulated in preeclampsia cases. We examined a total of 60 placentas from women that had given birth to female or male offspring in the University Hospital Augsburg. We investigated ten acute COVID-19 females, ten acute COVID-19 males, ten post-COVID-19 females, ten post-COVID-19 males, ten female term controls, and ten male term controls. Immunohistochemical staining against CD68, CD163, and PD-L1 was performed and the expression of the markers was evaluated with an immunoreactive score (percentage score). Identity of CD163- or PD-L1 expressing cells was analyzed by double immune fluorescence analyses. In opposite to PE, CD163 positive maternal macrophages are significantly upregulated in the decidua of male acute COVID-19 placentas. PD-L1 is significantly upregulated on male acute- and post-COVID-19 decidual immune cells and on male post-COVID-19 extravillous trophoblast cells. Surprisingly the observed effects are related to the fetal gender as they were not observed in female offsprings. Further investigation is necessary to analyze especially the imprinting effect of this infection.
CD24 is a mucin-like glycoprotein expressed on trophoblast cells and endothelial tissue of first and third trimester placentas. As an immune suppressor, CD24 may contribute to maternal immune tolerance to the growing fetus. CD24 is known to interact with the sialic acid-binding immunoglobulin-type lectins (Siglecs), specifically siglec-10. The aim of this study was to investigate the expression of both, CD24 and siglec-10 on placental tissue slides from acute covid patients, patients who survived a covid-19 infection and normal term controls. For the evaluation of CD24 & siglec-10 we used a total of 60 placentas, 10 acute covid-19 female, 10 acute covid-19 male, 10 post-covid-19 female, 10 post-covid-19 male, 10 female term controls and 10 male term controls. Immunohistochemical staining against CD24 and siglec-10 was performed and the expression of both markers was done with an immunoreactive score (IRS). Identity of CD24- or siglec-10 expressing cells was analyzed by double immune fluorescence analyses. The expression of CD24 is significantly downregulated on the extravillous trophoblast and on Hofbauer cells of female acute covid placentas. In the contrary, CD24 is significantly upregulated on male post-covid-19 Hofbauer cells. The CD24-ligand siglec-10 is significantly downregulated in post-covid-19 Hofbauer cells independently of fetal sex, whereas it shows significant higher expression in control female Hofbauer cells. CD24 and its ligand siglec-10 are differentially expressed in placentas of patients who survived a covid-19 infection. Surprisingly this effect is related to the fetal gender. Further investigation is necessary to analyze especially the imprinting effect of this infection.
Preeclampsia is a disorder of pregnancy characterized by endothelial dysfunction, abnormal placentation, systemic inflammation, and altered immune reaction. The aim of this study was to investigate the immune checkpoint molecules TIM-3 and Gal-9 on macrophages and Hofbauer cells (HBC) in the placenta of preeclampsia patients. Immunohistochemistry and Immunofluorescence was used to characterize the expression of the macrophage markers CD68 and CD163, CK7 and the proteins TIM-3 and Gal-9 in the placentas of preeclampsia patients comparing it to the placentas of healthy pregnancies. Double immunofluorescence staining (TIM-3 with CD3/CD19/CD56) was used to analyze the TIM-3 expression on other immune cells (T cells, B cells, NK cells) within the chorionic villi. The expression of TIM-3 on decidual macrophages did not significantly differ between the preeclamptic and the control group (p = 0.487). When looking at the different offspring we saw an upregulation of TIM-3 expression on decidual macrophages in preeclamptic placentas with female offspring (p = 0.049). On Hofbauer cells within the chorionic villi, the TIM-3 expression was significantly downregulated in preeclamptic cases without a sex-specific difference (p < 0.001). Looking at the protein Gal-9 the expression was proven to be downregulated both, on decidual macrophages (p = 0.003) and on Hofbauer cells (p = 0.002) within preeclamptic placentas compared to healthy controls. This was only significant in male offspring (p < 0.001 and p = 0.013) but not in female offspring (p = 0.360 and p = 0.068). While TIM-3 expression within the extravillious trophoblast and the syncytiotrophoblast was significantly downregulated (p < 0.001 and p = 0.012) in preeclampsia, the expression of Gal-9 was upregulated in (p < 0.001 and p < 0.001) compared to healthy controls. The local variations of the immune checkpoint molecules TIM-3 and Gal-9 in the placenta may contribute to the inflammation observed in preeclamptic patients. It could therefore contribute to the pathogenesis and be an important target in the treatment of preeclampsia.
Background
The therapy concepts that target several members of krüppel like factor (KLF) family have been achieved in breast cancer (BC). However, the role of KLF11 in BC remains unclear. This study explored the prognostic significance of KLF11 in BC patients and investigated its functional roles in this malignancy.
Methods
Immunohistochemistry (IHC) staining of KLF11 in 298 patients’ samples was performed to determine the prognostic role of the KLF11. Then the protein level was correlated to clinicopathological characteristics and survival outcomes. Afterward, the function of KLF11 was explored in vitro with siRNA-mediated loss-of-function of cell viability, proliferation, and apoptosis.
Results
From the cohort study, we found that the expression of KLF11 was positively associated with highly proliferative BC of BC. Furthermore, prognostic analysis demonstrated that KLF11 was an independent negative factor for disease-free survival (DFS) and distant-metastasis-free survival (DMFS) of BC. The KLF11-related prognostic model for DFS and DMFS showed high accuracy in predicting the 3-,5- and 10 -year survival probability of BC patients. Additionally, the knockdown of KLF11 inhibited cell viability and proliferation, as well as induced cell apoptosis in MCF7 and MDA-MB-231 cells, while only inhibited cell viability and induced cell apoptosis in SK-BR-3 cells.
Conclusions
Our study indicated that targeting KLF11 is an interesting therapeutic concept and further research could lead to a new therapeutic improvement in BC, especially in highly aggressive molecular subtypes.
Preeclampsia is a pregnancy-specific disease characterized by abnormal placentation, endothelial dysfunction, systemic inflammation and a disruption of the immune system. The goal of this study was to characterize the PD-1/PD-L1 system, an important immune checkpoint system, on macrophages and Hofbauer cells (HBC) in the placenta of preeclamptic patients. The expression of the macrophage markers CD68 and CD163 and the proteins PD1 and PD-L1 in the placenta of preeclamptic patients and healthy controls was examined by immunohistochemistry and immunofluorescence. The numbers of CD68-positive and CD163-positive macrophages were significantly downregulated in the decidua (p = 0.021 and p = 0.043) and the chorionic villi (p < 0.001 and p < 0.001) of preeclamptic patients. The majority of macrophages in the decidua and the chorionic villi were identified to be CD163-positive, indicating a predominantly M2-polarisation. The expression of PD1 on maternal macrophages of the decidua (p < 0.001) and on Hofbauer cells (p < 0.001) was shown to be significantly lower in preeclampsia. The expression of PD-L1 was proven to be downregulated on maternal macrophages in the decidua of preeclamptic patients (p = 0.043). This difference was only caused by a downregulation of PD-L1 expression in male offspring (p = 0.004) while there was no difference in female offspring (p = 0.841). The variation of the immune checkpoint molecules PD1 and PD-L1 in preeclampsia might play an important role in the development of inflammation seen in preeclamptic patients. It might thereby be an important target in the therapy of preeclampsia.
