Upregulation of exofacial peroxiredoxin-thioredoxin system of lymphocytes and monocytes in preeclampsia.

OBJECTIVES: An imbalanced redox homeostasis resulting in oxidative stress is present in preeclampsia. Peroxiredoxin-1 (PRDX1) and thioredoxin-1 (TRX1) regulatory enzymes are also contributing to the redox homeostasis, but were not investigated so far in preeclampsia. Thus, we have aimed to characterize PRDX1, TRX1 and oxidative stress biomarkers in blood samples of pregnant women with preeclampsia. STUDY DESIGN: Twelve patients with preeclampsia (PE) were enrolled into the study. Seven third trimester healthy pregnant women (HP) were accepted as control group. MAIN OUTCOME MEASURES: Peripheral venous blood samples of healthy and preeclamptic pregnant women were analyzed. Plasma level of advanced oxidation protein products (AOPP) was determined by spectrophotometry. The exofacial PRDX1 and TRX1 expression of lymphocytes and monocytes was detected by flow cytometry. RESULTS: The plasma AOPP level was significantly higher in preeclampsia compared to the healthy pregnant group. Significantly higher percentage of PRDX1 and TRX1 expressing lymphocytes and monocytes were detected in the blood samples of preeclamptic women compared to healthy pregnant controls. The ratio of circulating PRDX1 and TRX1 expressing lymphocytes and monocytes showed a significant inverse correlation with the birth weight of newborns. CONCLUSIONS: We have revealed that the level of advanced oxidation protein products is increased and the exofacial peroxiredoxin-1 and thioredoxin-1 system in lymphocytes and monocytes is upregulated in preeclampsia. In addition, the ratio of peroxiredoxin-1 and thioredoxin-1 positive circulating lymphocytes and monocytes correlates inversely with the neonatal birth weight, which finding indicates that pregnancies complicated by intrauterine growth restriction are accompanied by a higher level of oxidative stress.

Altered Immune Response and Implantation Failure in Progesterone-Induced Blocking Factor-Deficient Mice.

Earlier data suggest that progesterone-induced blocking factor (PIBF) is involved in implantation. The present study therefore aims to investigate the consequences of functional PIBF deficiency during the peri-implantation period. CD1 female mice were injected intraperitoneally with 2 µg anti-PIBF monoclonal antibody on days 1.5 and 4.5 of pregnancy. The number of implantation sites and resorption rates were recorded on day 10.5. PIBF+ decidual NK cells and B cells were detected by immunohistochemistry or immunofluorescence. Decidual and peripheral NK activity was assessed by flow cytometry. A prime PCR array was used for determining the differential expression of genes involved in lymphocyte activation and Th1 or Th2 differentiation in CD4+ and CD8+ spleen cells from pregnant anti-PIBF-treated and control mice. Anti-PIBF treatment in the peri-implantation period resulted in impaired implantation and increased resorption rates in later pregnancy. The number of PIBF+ decidual NK cells decreased, while both decidual and peripheral NK activity increased in the anti-PIBF-treated mice. B cells were absent from the resorbed deciduas of anti-PIBF-treated mice. The genes implicated in T cell activation were significantly downregulated in CD4+ and increased in CD8+ of the anti-PIBF-treated animals. The gene for IL-4 was significantly downregulated in CD4+ cells while that of IL-12A was upregulated in CD8+ cells of anti-PIBF-treated animals. These data suggest that the lack of PIBF results in an impaired T cell activation, together with Th1 differentiation and increased NK activity, resulting in implantation failure.

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

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-1ß, 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.