The Role of the Immune Checkpoint Molecules PD-1/PD-L1 and TIM-3/Gal-9 in the Pathogenesis of Preeclampsia-A Narrative Review.

Preeclampsia is a pregnancy-specific disease which is characterized by abnormal placentation, endothelial dysfunction, and systemic inflammation. Several studies have shown that the maternal immune system, which is crucial for maintaining the pregnancy by ensuring maternal-fetal-tolerance, is disrupted in preeclamptic patients. Besides different immune cells, immune checkpoint molecules such as the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1 system) and the T-cell immunoglobulin and mucin domain-containing protein 3/Galectin-9 (TIM-3/Gal-9 system) are key players in upholding the balance between pro-inflammatory and anti-inflammatory signals. Therefore, a clear understanding about the role of these immune checkpoint molecules in preeclampsia is essential. This review discusses the role of these two immune checkpoint systems in pregnancy and their alterations in preeclampsia.

The expression of TIM-3 and Gal-9 on macrophages and Hofbauer cells in the placenta of preeclampsia patients.

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.

The programmed cell death protein 1 (PD1) and the programmed cell death ligand 1 (PD-L1) are significantly downregulated on macrophages and Hofbauer cells in the placenta of preeclampsia patients.

Preeclampsia is a pregnancy-specific disease which is characterized by abnormal placentation, endothelial dysfunction, systemic inflammation and 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 as well as the proteins PD1 and PD-L1 in the placenta of preeclamptic patients was examined by immunohistochemistry and immunofluorescence in comparison to the placenta of healthy pregnancies. The numbers of CD68-positive and CD163-positive macrophages were significantly downregulated in the decidua (p = 0.021 and p = 0.043) and in 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. Looking at the protein PD-L1 the expression 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.

Prevalence of methicillin-sensitive, methicillin-resistant Staphylococcus aureus, and extended-spectrum beta-lactamase-producing Escherichia coli in newborns: a cross-sectional study.

BACKGROUND: The prevalence of antimicrobial-resistant bacteria and methicillin-sensitive Staphylococcus aureus (MSSA) in healthy newborns and the role of maternal transmission are scarcely discussed. OBJECTIVES: The objective of this study was to evaluate the prevalence of MSSA, MRSA, and ESBL among healthy newborns. Additionally, mother-to-newborn transmission rates were investigated as well as antibiotic susceptibility of MSSA, MRSA, and ESBL isolates. METHODS: Swabs of 658 newborns and their mothers were collected to investigate the presence of MSSA, MRSA, and ESBL. Swabs were taken from the nose and umbilicus immediately after birth. Additional swabs were taken from the nose, perianal area, and umbilicus 3 days after birth. Samples were screened and further characterized using culture and molecular methods. RESULTS: Prevalence of MSSA, MRSA, and ESBL colonization was 10.9, 0.5, and 2.6%, respectively. There was no association between the colonization status of the newborn and infections at any time point. Mother-to-newborn transmission rates (confirmed by PFGE) were 53.6% for MSSA/MRSA and 100% for ESBL. Maternal carriage of MSSA, MRSA, or ESBL was a risk factor for colonization of the newborn. Some isolates were resistant to the antibiotics recommended for therapy, including clindamycin and daptomycin for MSSA/MRSA isolates and ertapenem, fosfomycin, and tigecyclin for ESBL isolates. CONCLUSION: No association between infections and the newborns' colonization status could be detected. Maternal colonization played an important role in newborn colonization, but not every case of colonization could be explained by mother-to-newborn transmission. General screening of pregnant women and healthy newborns in the absence of other risk factors is not necessary. To prevent the possibility of transmission in the healthcare setting, professionals, pregnant women, parents, hospital visitors, and obstetricians should receive regular training on appropriate hygiene measures. With regard to the emergence of resistance to recommended antibiotics, an antibiogram should be conducted before treating MSSA/MRSA/ESBL infections to ensure the efficacy of the antibiotics.

Hospitalization cost at childbirth: Health parameters and colonization with antimicrobial resistant bacteria and methicillin susceptible Staphylococcus aureus.

OBJECTIVE: Antimicrobial resistant bacteria (AMR) are of public health and economic relevance. However, there is a lack of data regarding AMR colonization in pregnant women and in newborns. Furthermore, there are few studies analyzing hospital's net income (revenues and costs). STUDY DESIGN: The cross-sectional study took place in two Bavarian clinics. Available data regarding women and newborns were collected using a standardized questionnaire, personal IDs and medical records in addition to AMR/MSSA screening. Economic data consisted of estimated hospitalization costs, calculated using a billing system called G-DRG (German-Diagnosis Related Groups) as well as real hospitalization costs (e.g. staff, medical and non-medical infrastructure costs). RESULTS: Data from 635 pregnant women and 566 newborns were included. While AMR colonization has shown no significant association with clinical complications, or net hospital income; primipara status and medical condition during pregnancy did. AMR colonization did not have a significant influence on the health status of pregnant women or of the newborns. Net hospital income for pregnant women was mostly negative in 2014. In 2014 and 2015 the majority of the cases had a net income between ±€ 1000. Newborns with clinical complications differed significantly in Apgar score at 1min, weight, body length and AMR colonization of the pregnant woman and/or the newborn (p<=0.05). CONCLUSION: Results indicate that colonization does not lead to increased costs during hospitalization considering real hospitalization costs as well as G-DRG estimated costs. Both DRG groups had similar MSSA and AMR prevalence and health status. In future studies, a Centralized Cost Accounting as billing method and an improved possibility of AMR coding in G-DRG catalog would be desirable.