Search

The extensive metabolism of estrogen hormones, where oxidized forms, structural isomers and conjugated products appear in many tissues locally as well as in systemic circulation, is believed to be associated with a number of diseases. Targeted estrogen metabolomic studies have been largely associated with postmenopausal, malignant advert immune conditions. Although the role of estriol in maintaining pregnancy and the biological activity of estrogen metabolites is known, a relatively small number of publications have addressed the formation and transformation of these compounds during pregnancy. The aim of this study is to present in detail the formation and progression of estrogen metabolites during pregnancy and to summarize the knowledge of their role in undesirable processes occurring during gestation. Orv Hetil. 2019; 160(26): 1007-1014.

Problem: To address the hypothesis that pre-eclampsia (PE) impacts the fetal immune system, we investigated the prevalence of distinct immune cell subsets along with plasma cortisol and cytokine levels in pre-term newborns of PE mothers., Method of Study: Cord blood and peripheral blood samples on the 1st, 3rd and 7th postnatal days of life were collected from 14 pre-term infants affected by PE and 14 non-PE pregnancies. We measured plasma cortisol and cytokine levels with immunoassays and assessed the prevalence of T, NK and DC subsets using flow cytometry., Results: The prevalence of CD4+ cells was lower in PE infants, while that of memory T cells was higher. Myeloid DCs had a lower prevalence in PE neonates. Cytokine and cortisol levels were lower in PE neonates., Conclusion: Our observations show that PE pregnancies are associated with altered newborn immune status during the first week of life., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Inappropriate activation of T lymphocytes plays an important role in perinatal complications. However, data on T lymphocyte activation markers of preterm infants is scarce. We investigated the association between gender, gestational and postnatal age, preeclampsia (PE), premature rupture of membranes (PROM) as well as prenatal steroid treatment (PS) and the frequency of activated T lymphocyte subsets (HLA-DR+, CD69+, CD25+, CD62L+) and major T lymphocyte subpopulations (CD4, CD8, Th1, Th2, naïve, memory) in peripheral blood during the first postnatal week in preterm infants., Results: Cord blood and peripheral blood samples were collected from 43 preterm infants on the 1st, 3rd, and 7th days of life. We assessed the frequency of the above T lymphocyte subsets using flow cytometry. The 'mixed effect model' was used to analyze the effects of clinical parameters on T lymphocyte markers. The frequency of CD25+ T lymphocytes was higher in PROM. The frequency of CD4+ and CD8+ cells and the CD4+/CD8+ cell ratio was decreased in PE. The frequency of CD62L+ T lymphocytes was higher in male compared with female infants. PS did not affect the frequency of the investigated markers. CD4+ CD25+ cells had a lower frequency at birth than on day 7. Th2 lymphocytes had a lower frequency on postnatal days 1 and 3 when compared to day 7., Conclusions: Our observations indicate that alterations affecting the expression of T lymphocyte activation markers are associated with the above factors and may play a role in the development of perinatal complications.

Problem: We determined the frequency of activated (CD11b+) monocytes expressing B7-1, B7-2, B7-H1, and B-7H2, and that of T cells and T helper cells expressing CD28, CTLA-4, PD-1, and ICOS in peripheral blood samples from normal pregnant (NP) and pre-eclamptic (PE) women. We also examined the intracellular expression of indoleamine-2,3-dioxygenase (IDO)., Method of Study: We measured the expression of the above markers using flow-cytometry in peripheral blood samples from 20 NP and 20 PE women in the third trimester., Results: The frequency of B7-1 and B7-2 expressing activated monocytes and that of IDO expressing T-lymphocytes was lower in PE than in NP., Conclusion: Lower expression of B7-1 and B7-2 proteins on peripheral monocytes in PE might indicate a secondary regulatory mechanism in response to the ongoing systemic maternal inflammation. IDO plays an important role in the pregnancy-specific immune tolerance, and might be a contributing factor in the pathogenesis of PE., (© 2013 John Wiley & Sons A/S.)

Problem: Regulatory T cells (Tregs) play an important role in the development of pregnancy-specific immune tolerance. We aimed to determine the peripheral frequency of a recently described Treg subpopulation, the CD4+ CD25- FoxP3+ Treg subset, and its correlation with the conventional CD4+ CD25high FoxP3+ Tregs in normal pregnancy (NP) and pre-eclampsia (PE) compared to non-pregnant (non-P) women. We also examined the proportion of the activated CD4+ CD25high FoxP3high Treg subset within conventional Treg cells., Method: We took peripheral blood samples from 20 PE, 20 NP, and 12 non-P women and determined the frequency of the above Treg subsets using flow cytometry., Results: The frequency of conventional CD4+ CD25high FoxP3+ Tregs and activated CD4+ CD25high FoxP3high Tregs, but also that of non-conventional CD4+ CD25- FoxP3+ Tregs was higher in NP compared to non-P women, but lower again in PE, reaching comparable levels to the non-P group. The ratios of CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ Treg subsets were constant in all three investigated groups., Conclusion: Our results indicate that the frequency of conventional and non-conventional Tregs alters simultaneously, and the presence in circulation of both of these Treg subsets is similarly important in the adequate development of pregnancy-specific immune tolerance., (© 2012 John Wiley & Sons A/S.)

Background: Preeclampsia is characterized by a maternal systemic inflammatory response and the impairment of maternal immune tolerance present in healthy pregnancy. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker increasingly used for the monitoring of systemic inflammation. We aimed to assess the levels of suPAR and other markers of systemic inflammation in preeclampsia compared to healthy pregnancy., Methods: We determined plasma suPAR, IL-6 and high sensitivity C-reactive protein (hs-CRP) levels in plasma samples of 62 healthy pregnant and 41 preeclamptic women in the third trimester of pregnancy., Results: Plasma suPAR levels were elevated in preeclampsia [3.18 (2.30-4.71) ng/mL vs. 2.02 (1.81-2.40) ng/mL, p=0.0001, median (interquartile range)]. IL-6 and hs-CRP levels were also higher compared with healthy pregnancy [5.99 (2.97-18.12) pg/mL vs. 1.41 (1.00-2.70) pg/mL, p=0.0001 and 6.60 (3.55-15.40) mg/L vs. 3.90 (2.10-7.25) mg/L, p=0.006, respectively, median (interquartile range)]. Linear regression analyses revealed an association between individual plasma suPAR and log IL-6 levels as well as log hs-CRP levels., Conclusions: suPAR levels are elevated in preeclampsia and vary in a narrower range compared with IL-6 and hs-CRP. ROC analysis indicated that monitoring of suPAR levels is a suitable tool for the detection of systemic inflammation in pregnancy.

Problem: Systemic inflammation is a dominant component in the pathogenesis of pre-eclampsia. Besides the imbalance of Th1 and Th2 cells, alterations of the prevalence of Th17 and regulatory T cells have also been suggested to contribute to inflammation. We aimed to describe the prevalence of these four CD4 lymphocyte subtypes in pre-eclampsia and normal pregnancy, along with that of IL-17-producing CD8 and NK cells., Method of Study: Twenty pre-eclamptic and 22 normal pregnant women were enrolled in this study. Using flow cytometry, we determined the prevalence of IL-17-producing cells among the CD4, CD8 and NK cell subsets. Furthermore, we measured the prevalence of CD4+ Tregs, and Th1/Th2 cells were characterized using cell surface chemokine receptor markers., Results: We demonstrated that there is a shift not only in the Th1/Th2 but also in the Th17/Treg balance favouring skewness towards a pro-inflammatory status in pre-eclampsia. The proportion of CD8 and NK cells that express IL-17 was also higher in pre-eclampsia., Conclusion: The prevalence of IL-17-producing CD4, CD8 and NK cells is elevated in pre-eclampsia, indicating that both the innate and adaptive arms of the immune system are involved in the development of the exaggerated maternal systemic inflammation observed in this pregnancy-specific disorder., (© 2011 John Wiley & Sons A/S.)

Preeclampsia (PE) is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive arms of the immune system. Granulysin is a cytolytic and pro-inflammatory molecule expressed by activated human cytotoxic T lymphocytes and natural killer (NK) cells. Recent data show that serum granulysin levels are elevated in preeclampsia. The purpose of this study was to determine whether the proportion of peripheral blood cytotoxic T lymphocytes and NK cells that express intracellular granulysin is altered in PE. Twenty-two preeclamptic patients and 29 healthy pregnant women were involved in this case-control study. Intracellular granulysin expression of lymphocytes was determined with flow cytometric examination. In healthy pregnant women, the majority of NK cells and a small fraction of cytotoxic T cells expressed granulysin in their cytoplasma (median (25-75 percentile): 53.5 (45.6-68.0)% and 13.8 (8.5-23.1)%, respectively). In PE, the percentage of granulysin-positive cytotoxic T lymphocytes was markedly increased, while the proportion of granulysin-producing NK cells was unchanged as compared to healthy pregnant women (for cytotoxic T cells: 34.1 (19.3-45.6)%, p<0.001; for NK cells: 57.2 (42.9-74.9)%, p>0.05). Maternal age of healthy pregnant women showed a significant inverse correlation with the frequency of granulysin-expressing NK cells (Spearman R=-0.44, p<0.05), while their BMI correlated positively with the proportions of granulysin-positive cytotoxic T cells and NK cells (Spearman R=0.43, p<0.05 for both). In conclusion, the majority of circulating NK cells but only a small population of cytotoxic T cells shows intracellular granulysin expression in normal pregnancy. In preeclampsia, the proportion of granulysin-producing cytotoxic T cells in the peripheral blood is markedly increased, which might contribute to the development of the pro-inflammatory Th1-type immune responses characteristics of the maternal syndrome of the disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to determine whether the proportion of galectin-1-expressing peripheral blood T and NK cells is altered in normal pregnancy and preeclampsia (PE). We also examined whether circulating levels of galectin-1 and anti-galectin-1 autoantibodies are affected in PE. Seventy preeclamptic patients, 75 healthy pregnant and 21 healthy non-pregnant women were involved in this study. Serum galectin-1 and anti-galectin-1 autoantibody levels were measured by ELISA. Intracellular galectin-1 expression of lymphocytes was determined with flow cytometry. Serum galectin-1 and anti-galectin-1 IgG levels did not differ significantly between the healthy pregnant and the PE group. In healthy pregnant women, significantly higher percentage of T and NK cells expressed gal-1 in their cytoplasma than in healthy non-pregnant women. However, the proportion of galectin-1-expressing peripheral blood T and NK cells was markedly decreased in PE compared to normal pregnancy, which might contribute to the activation of innate and acquired immune cells., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to determine the proportion of circulating T and natural killer (NK) cells that express intracellular vascular endothelial growth factor (VEGF) in women with preeclampsia compared to those with a normal pregnancy., Study Design: In all, 24 preeclamptic patients and 30 healthy pregnant women were involved in this case-control study. Intracellular VEGF expression of unstimulated lymphocytes was determined with flow cytometric examination., Results: In healthy pregnant women, the majority of both T and NK cells expressed VEGF in their cytoplasma (median, 79.9%; 25-75 percentile, 73.7-87.0 and median, 78.3%; 25-75 percentile, 64.1-85.3, respectively). Furthermore, CD4(+) helper and CD8(+) cytotoxic T cells showed a similar pattern of VEGF expression in normal pregnancy. However, the proportion of VEGF-expressing peripheral blood T (both helper and cytotoxic) and NK cells was markedly decreased in preeclampsia (for T cells: median, 51.6%; 25-75 percentile, 40.1-60.0; P < .001; for NK cells: median, 45.2%; 25-75 percentile, 27.4-64.0; P < .001)., Conclusion: Our results suggest decreased production of VEGF by circulating T and NK cells in preeclampsia, which might contribute to the development of the generalized endothelial dysfunction characteristic of the maternal syndrome of the disease., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Background: Plasma iron is increased in preeclampsia (PE) when compared to healthy pregnant women. This is in contrast to inflammation characteristic for PE. The link between iron homeostasis and inflammation is hepcidin. Our goal was to describe hepcidin concentrations and its association with iron homeostasis in PE., Methods: We obtained peripheral blood samples from 30 preeclamptic [gestational age: 36.5 (24-40) weeks] and 37 healthy pregnant women [gestational age: 36 (28-39) weeks] to determine plasma hepcidin and interleukin-6 (IL-6) concentrations, complete blood cell counts and parameters of iron homeostasis [plasma iron, transferrin and ferritin levels and total iron binding capacity (TIBC)]. Hepcidin was measured using mass spectrophotometry. The Mann-Whitney test was used for statistical analysis., Results: Plasma hepcidin, IL-6, iron and ferritin concentrations were increased (p<0.05 for all), whereas plasma transferrin, TIBC and mean corpuscular hemoglobin concentrations were lower (p<0.05 for all) in PE compared to healthy pregnant women. No differences were seen in the other parameters investigated., Conclusions: Plasma iron concentrations are increased despite high hepcidin concentrations in PE. This might indicate a resistance to the iron-decreasing action of hepcidin.

Systemic inflammation is characteristic for preeclampsia (PE). A hypothesis for immune dysregulation is that the function of regulatory T cells (CD4(+)FoxP3(+), Tregs) inhibiting the activation of lymphocytes is impaired. We investigated the proportion of Tregs and their cellular network in preeclamptic women. Fifteen preeclamptic and 17 healthy pregnant women were enrolled in the 32nd gestational week (median age 29 (range 22-45) and 32 (range 26-38) years, respectively). PE was diagnosed according to international criteria at a median of 30 gestational weeks (range 21-31). Peripheral blood was taken and blood mononuclear cells were isolated. Flow cytometry was used to determine the proportion of regulatory (CD4+FoxP3+) T cells, lymphoid and myeloid dendritic cells, natural killer and natural killer T cells, naive and memory and activated CD4+ and CD8+cells. The proportion of Tregs and that of naive CD4(+)CD45RA(+) cells was lower in preeclamptic than in control women (p=0.025, p=0.04, respectively). The proportion of other investigated cell types did not differ. Low Treg numbers may support the notion that PE shares similar features to autoimmune disorders. Low Treg numbers are not reflected in the proportion of activated lymphocytes, at least in this stage of pregnancy. This does not exclude, however, the functional alterations of these cell types.

Objective: To investigate the association of functional E and P selectin polymorphisms with severe preeclampsia., Study Design: P-selectin Thr715Pro and E-selectin Serl28Arg polymorphism were determined with the polymerase chain reaction in 126 women with severe preeclampsia and in 106 healthy pregnant women. Genotype distribution and allele prevalence of both groups were compared. Regression analysis was used to analyze the association between disease characteristics and genotype., Results: Genotype distributions and the allele prevalence were similar in the tested populations. Furthermore, the genotypes investigated had no impact on the risk of eclampsia of the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Multiple linear regression analysis identified the P-selectin 715Pro allele as an independent determinant of the time of onset of hypertension (p = 0.034) along with maternal age, smoking and body mass index before pregnancy., Conclusion: The polymorphisms tested are not associated with the risk of severe preeclampsia.

Aim: The aim was to evaluate familial early-onset cardiovascular disorders as potential risk factors for severe preeclampsia., Study Design: A case-control study was carried out by interviewing 162 primiparous severely preeclamptic women and 521 primiparous healthy control patients after delivery to determine the frequency of cardiovascular disorders (chronic hypertension, myocardial infarction, stroke) developed before the age of 50 among their parents. The chi2-test was utilized to estimate odds ratios (OR) and 95% confidence intervals (95% CI). The association was adjusted for pre-pregnancy body mass index, maternal age, and smoking habits before pregnancy using logistic regression analysis., Results: Maternal and paternal early-onset chronic hypertension (adjusted OR: 3.84, 95% CI: 2.25-6.54; and adjusted OR: 3.26, 95% CI: 1.76-6.05) as well as paternal early-onset myocardial infarction (adjusted OR: 3.33; 95% CI: 1.51-7.32) were independent risk factors for severe preeclampsia. Early-onset stroke affected only the fathers of severely preeclamptic patients. Among the severely preeclamptic patients a positive family history of cardiovascular disorders developed before the age of 50 increased the risk of early-onset preeclampsia (developing before the 32nd gestational week) by 5.05-fold (95% CI: 3.08-8.31) compared with the control group., Conclusion: Our results suggest that the presence of familial early-onset cardiovascular disorders is a predisposing factor for severe preeclampsia.

Several lines of evidence support the hypothesis that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of pre-eclampsia (PE). VEGF is a key component in the regulation of vascular remodelling and the survival of cytotrophoblasts in the placenta. In this case-control study, we aimed to test whether VEGF genetic polymorphisms are associated with the risk of severe PE. We enrolled 84 nulliparous pregnant women with severe PE (PE group). Their VEGF G(+405)C and VEGF C(-2578)A genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) from venous blood samples and were compared with the corresponding VEGF genotypes of 96 nulliparous patients with uncomplicated pregnancies (control group). Carriers of the VEGF(+405)G allele occurred less frequently in PE than in the control group [P = 0.039; adjusted odds ratio (aOR) = 0.28, range: 0.08-0.93]. Hypertension and proteinuria were diagnosed earlier (by 1.6 weeks and 1.9 weeks, respectively) in PE patients with VEGF(-2578)A only after adjustment of this association for risk factors of PE. Our results suggest that carriers of VEGF(+405)G allele have a decreased susceptibility to PE and that the progression of PE may be modified by the presence of VEGF(-2578)A allele. Nevertheless, the clinical significance of these findings remains to be determined.