Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age

Madar-Shapiro, Liora; Karady, I; Trahtenherts, Alla; Syngelaki, A.; Akolekar, Ranjit; Poon, Liona C.; Cohen, Rachel E.; Sharabi-Nov, Adi; Huppertz, Berthold; Sammar, Marei; Juhász, Kata; Than, Nándor Gábor; Papp, Zoltán; Romero, Roberto; Nicolaides, Kypros H.; Meiri, Hamutal

doi:10.1159/000477933

Cited by 16 publications

(25 citation statements)

References 57 publications

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“… 5 PP13 serum levels in these women vanished very slowly after delivery and could be determined for 5–6 weeks postpartum and occasionally longer. 5 A recent study by Madar-Sharipo et al 36 has shown that combining the presence of the A/A genotype in the −98 site of the PP13 promoter with obesity, African (black) origin, and history of preeclampsia significantly increases the accuracy of predicting the risk of preeclampsia. 28 The determination of low serum levels of PP13 in early pregnancy contributes to the prediction of preeclampsia as well.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits

Drobnjak¹,

Meiri²,

Mandalà³

et al. 2018

DDDT

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IntroductionHuman placental protein 13 (PP13) is a galectin predominantly expressed by the placenta. Low serum concentrations of PP13 in early pregnancy indicate a higher risk of developing preeclampsia.MethodsThe pharmacokinetic disposition and bioavailability of PP13 were determined by single intravenous and subcutaneous administration to 12 healthy New Zealand White rabbits. The serum pharmacokinetic values were determined by enzyme-linked immunosorbent assay, and are best described by a two-compartment model.ResultsBoth volume of distribution and the area under the curve were dose dependent for the intravenous group (p<0.01). PP13 elimination half-life was also found to be different between the groups (p<0.01). The bioavailability of PP13 following subcutaneous administration was found to be 57%.ConclusionThis study shows that the concentration of total PP13 released into the maternal circulation during pregnancy might be much higher than previously estimated.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits

Drobnjak¹,

Meiri²,

Mandalà³

et al. 2018

DDDT

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“…The expression of these galectins is dependent on trophoblast differentiation, and this developmentally regulated process in the trophoblast emerged during primate evolution (110). Of importance, Gal-13 is secreted from the syncytiotrophoblast into the maternal circulation, and low Gal-13 concentration in the maternal circulation in the first trimester was found in women who subsequently developed preterm preeclampsia (115–122), a severe obstetrical syndrome with a strong systemic immune dysregulation (51, 82, 86, 123–128) that already exists in the first trimester (129). Our studies have also shown that the placental expression of Gal-13 and Gal-14 is down-regulated in preterm preeclampsia (81, 110, 113, 129), where the placental pathology and the pro-inflammatory changes are similar to that of miscarriage (130–135).…”

Section: Introductionmentioning

confidence: 99%

Placental Galectins Are Key Players in Regulating the Maternal Adaptive Immune Response

et al. 2019

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Galectins are potent immunomodulators that regulate maternal immune responses in pregnancy and prevent the rejection of the semi-allogeneic fetus that also occurs in miscarriages. We previously identified a gene cluster on Chromosome 19 that expresses a subfamily of galectins, including galectin-13 (Gal-13) and galectin-14 (Gal-14), which emerged in anthropoid primates. These galectins are expressed only by the placenta and induce the apoptosis of activated T lymphocytes, possibly contributing to a shifted maternal immune balance in pregnancy. The placental expression of Gal-13 and Gal-14 is decreased in preeclampsia, a life-threatening obstetrical syndrome partly attributed to maternal anti-fetal rejection. This study is aimed at revealing the effects of Gal-13 and Gal-14 on T cell functions and comparing the expression of these galectins in placentas from healthy pregnancies and miscarriages. First-trimester placentas were collected from miscarriages and elective termination of pregnancies, tissue microarrays were constructed, and then the expression of Gal-13 and Gal-14 was analyzed by immunohistochemistry and immunoscoring. Recombinant Gal-13 and Gal-14 were expressed and purified, and their effects were investigated on primary peripheral blood T cells. The binding of Gal-13 and Gal-14 to T cells and the effects of these galectins on apoptosis, activation marker (CD25, CD71, CD95, HLA-DR) expression and cytokine (IL-1β, IL-6, IL-8, IL-10, IFNγ) production of T cells were examined by flow cytometry. Gal-13 and Gal-14 are primarily expressed by the syncytiotrophoblast at the maternal-fetal interface in the first trimester, and their placental expression is decreased in miscarriages compared to first-trimester controls. Recombinant Gal-13 and Gal-14 bind to T cells in a population- and activation-dependent manner. Gal-13 and Gal-14 induce apoptosis of Th and Tc cell populations, regardless of their activation status. Out of the investigated activation markers, Gal-14 decreases the cell surface expression of CD71, Gal-13 increases the expression of CD25, and both galectins increase the expression of CD95 on T cells. Non-activated T cells produce larger amounts of IL-8 in the presence of Gal-13 or Gal-14. In conclusion, these results show that Gal-13 and Gal-14 already provide an immunoprivileged environment at the maternal-fetal interface during early pregnancy, and their reduced expression is related to miscarriages.

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“…Dr. Hans Bohn was one of the most eminent scientists of the field, who purified more than 50 proteins from the human placenta, which he named sequentially, and generated highly specific antibodies against them (Than, Bohn & Szabo, 1993). Later studies showed that many of the so-called soluble PPs secreted from the placenta into the maternal circulation, such as Placental Protein 5 (PP5, tissue factor pathway inhibitor-2, TFPI-2) or Placental Protein 13 (PP13, galectin-13), have important roles in placental functions and diagnostic significance in pregnancy complications (Than et al, 1999, 2004, 2008, 2011, 2014a, 2014b, 2018; Visegrady et al, 2001; Romero et al, 2008; Balogh et al, 2011; Madar-Shapiro et al, 2018; Karaszi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Proteomic identification of membrane-associated placental protein 4 (MP4) as perlecan and characterization of its placental expression in normal and pathologic pregnancies

Szenasi

Tóth

Balogh

et al. 2019

PeerJ

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Background More than 50 human placental proteins were isolated and physico-chemically characterized in the 70–80s by Hans Bohn and co-workers. Many of these proteins turned to have important role in placental functions and diagnostic significance in pregnancy complications. Among these proteins was membrane-associated placental protein 4 (MP4), for which identity or function has not been identified yet. Our aim was to analyze the sequence and placental expression of this protein in normal and complicated pregnancies including miscarriage, preeclampsia and HELLP syndrome. Methods Lyophilized MP4 protein and frozen healthy placental tissue were analyzed using HPLC-MS/MS. Placental tissue samples were obtained from women with elective termination of pregnancy (first trimester controls, n = 31), early pregnancy loss (EPL) (n = 13), early preeclampsia without HELLP syndrome (n = 7) and with HELLP syndrome (n = 8), late preeclampsia (n = 8), third trimester early controls (n = 5) and third trimester late controls (n = 9). Tissue microarrays were constructed from paraffin-embedded placentas (n = 81). Slides were immunostained with monoclonal perlecan antibody and evaluated using light microscopy and virtual microscopy. Perlecan was also analyzed for its expression in placentas from normal pregnancies using microarray data. Results Mass spectrometry-based proteomics of MP4 resulted in the identification of basement membrane-specific heparan sulfate proteoglycan core protein also known as perlecan. Immunohistochemistry showed cytoplasmic perlecan localization in syncytiotrophoblast and cytotrophoblasts of the villi. Perlecan immunoscore decreased with gestational age in the placenta. Perlecan immunoscores were higher in EPL compared to controls. Perlecan immunoscores were higher in early preeclampsia without and with HELLP syndrome and lower in late preeclampsia than in respective controls. Among patients with preeclampsia, placental perlecan expression positively correlated with maternal vascular malperfusion and negatively correlated with placental weight. Conclusion Our findings suggest that an increased placental perlecan expression may be associated with hypoxic ischaemic injury of the placenta in miscarriages and in early preeclampsia with or without HELLP syndrome.

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Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age

Cited by 16 publications

References 57 publications

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits

Placental Galectins Are Key Players in Regulating the Maternal Adaptive Immune Response

Proteomic identification of membrane-associated placental protein 4 (MP4) as perlecan and characterization of its placental expression in normal and pathologic pregnancies

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