Increased circulating paternal antigen-specific IFN-gamma- and IL-4-secreting cells during pregnancy in allergic and non-allergic women

INTRODUCTION: Allergic women have been reported to give birth to more children than non-allergic women, speculatively explained by the former's predisposition for Th2 polarization, possibly favoring pregnancy. AIM: The aim of this study was to test the hypothesis that allergy is associated with more Th2-deviated responses to paternal antigens throughout pregnancy. METHODS: Blood samples were collected on six occasions during pregnancy and two occasions postpartum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Eleven women fulfilled the strict criteria for allergy (allergic symptoms and circulating IgE antibodies to inhalant allergens) and 23 were strictly non-allergic (non-sensitized without symptoms). The numbers of blood mononuclear cells secreting IFN-gamma and IL-4, spontaneously and in response to paternal alloantigens, were compared between the groups. RESULTS: The numbers of spontaneously as well as paternal antigen-induced IFN-gamma- and IL-4-secreting cells were similar in allergic and non-allergic pregnant women on all occasions. A similar increase in the numbers of both IFN-gamma- and IL-4-secreting cells were found in allergic and non-allergic women during pregnancy, both regarding spontaneous and paternal antigen-induced secretion. CONCLUSIONS: This study does not support the hypothesis of a more pronounced Th2-deviation to paternal antigens in allergic pregnant women compared with non-allergic pregnant women, as measured by number of cytokine-secreting cells. The observed increase of both IFN-gamma- and IL-4-secreting cells during normal pregnancy may be interpreted as a Th2-situation, since the effects of IL-4 predominate over the effects of IFN-gamma.     

Retrospective comparison of blood pressure course during preeclamptic and matched control pregnancies

A decrease in systemic blood pressure by midtrimester of normal pregnancy has been observed by many investigators. To examine the timing of onset of this decline and to study early behavior of blood pressure in pregnancies complicated by preeclampsia, we reviewed the outpatient charts of all patients with preeclampsia who received prenatal care at our clinics during the past 3 years. The 30 patients who met our criteria for preeclampsia were matched for age, race, and parity with normotensive control subjects. We found that in normal pregnancies, decline in blood pressure occurred before the second trimester and blood pressure remained low throughout gestation, rising insignificantly near term. Both systolic and diastolic blood pressures were significantly higher (p less than 0.05) for patients with preeclampsia than for normal control subjects beginning in the first trimester. This difference persisted throughout pregnancy and was also present at the 6-week postpartum visit (p less than 0.025).     

In-situ detection of both inflammatory and anti-inflammatory cytokines in resting peripheral blood mononuclear cells during pregnancy

INTRODUCTION: Local and possibly systemic curtailment of the maternal immune response is important for a successful pregnancy. Although the local milieu at the utero-placental interface is likely to harbor the most prominent alterations, it is suggested, at least in mice, that systemic immunity is also tolerized during pregnancy. In the present study, we investigated mRNA expression of the key immunomodulatory cytokines; interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma during normal pregnancy. MATERIAL AND METHODS: In-situ hybridization (ISH) of cytokine mRNA in resting peripheral blood mononuclear cells (PBMCs) was used to detect the number of cells spontaneously expressing cytokines. Eleven women with normal gestations were followed during pregnancy as well as 8 weeks postpartum, and compared with 10 non-pregnant healthy controls. RESULTS: The numbers of IFN-gamma and IL-4 mRNA expressing cells were found to be significantly increased during pregnancy and postpartum compared with non-pregnant controls. Pregnant women and non-pregnant controls did not differ in their expression of TNF-alpha and IL-10. CONCLUSION: Our studies demonstrated increased numbers of both IFN-gamma and IL-4 mRNA expressing cells in blood suggesting that systemic immunomodulation, albeit partial, takes place during normal pregnancy. It is proposed that enhanced IL-4 expression, possibly in concert with other elevated anti-inflammatory immunomodulatory cytokines, curtail the potentially hazardous effects of IFN-gamma on systemic immunity during pregnancy.     

正常妊娠和子痫前期患者外周血树突细胞亚群的变化

目的:探讨树突细胞(DCs)及其亚群在正常妊娠和子痫前期患者间的变化,及与Th1/Th2型反应的关系。方法:选取正常妊娠孕妇25例、子痫前期患者17例和正常未孕妇女15例,用流式细胞术检测3组外周血树突细胞及其髓样(MDC)和淋巴样(PDC)亚群,比较其数量和比值在妊娠前后及子痫前期患者的变化,并与Th1/Th2型细胞因子的含量比较。结果:与正常妊娠早期和晚期相比,妊娠中期MDC和PDC数量减少,MDC/PDC比值升高,妊娠早、晚期相比无显著差异。与正常晚期妊娠妇女比较,子痫前期患者PDC数量减少,MDC数量改变不明显,MDC/PDC比值升高,两组相比差异显著。与正常晚期妊娠妇女相比较,子痫前期患者Th1型细胞因子IL-2含量增加,IFN-γ无显著差异,Th2型细胞因子IL-10减少,IL-2/IL-10、IFN-γ/IL-10比值升高。结论:DCs在正常妊娠的不同阶段其数量和亚群发生变化,子痫前期患者出现PDC减少和MDC/PDC比值升高现象,并与Th1/Th2型细胞因子的变化趋势一致。     

Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.     

Distribution of Th1 and Th2 cell populations in human peripheral and decidual T cells from normal and anembryonic pregnancies

OBJECTIVE: To examine whether maternal immune responses during normal pregnancy are Th2 biased and whether there are specific changes when anembryonic pregnancy occurs. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology at a university hospital. PATIENT(S): We studied 32 pregnant women receiving elective abortions of normal pregnancies and 35 women with anembryonic pregnancies between 6 weeks and 10 weeks of gestational age. INTERVENTION(S): Using the multilabeling capability of three-color flow cytometry, it is possible to measure intracellular cytokines and cell surface markers simultaneously to determine which cells are the cytokine-producing cells. MAIN OUTCOME MEASURE(S): We examined the extent and proportion of mononuclear cells expressing specific T-cell surface markers and cytokines, interferon gamma, and interleukin 4 in the peripheral blood and deciduae. Secreted cytokines in the supernatants after 24-hour culture were also compared. RESULT(S): During the unstimulated status, the proportion of IL-4-secreting cells significantly exceeded that of IFN-gamma-secreting cells in the peripheral blood and decidua in normal pregnancies and was significantly decreased when anembryonic pregnancies occurred. Consequently, the Th1/Th2 ratios were increased during anembryonic pregnancies. However, after 24-hour culture, only another Th2-type cytokine, IL-10, was markedly increased and exceeded IFN-gamma secretion in cultures from both the peripheral blood and decidua in normal pregnancies. CONCLUSION(S): The decidual T lymphocytes are Th2 predominant. When anembryonic pregnancy occurs, this Th2 predominance disappears.     

Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women

The soluble VEGF receptor, sFlt-1 (otherwise referred to as sVEGFR-1), has been implicated in the pathogenesis of preeclampsia. The preeclamptic placenta has been previously demonstrated to produce high levels of the soluble VEGF receptor. Here we tested the hypothesis that peripheral blood mononuclear cells (PBMCs) may also represent an additional source for circulating sFlt-1 during normal and preeclamptic pregnancies. We first demonstrate that preeclamptic placentae show five-fold increased Flt-1 and sFlt-1 mRNA levels. We also show that the Flt-1 and sFlt-1 levels are eight-fold higher in preeclamptic placentae if we collect biopsies without rinsing them in saline to remove excess blood. Cultured villous explants from women with preeclampsia failed to show the increased amount of Flt-1 and sFlt-1 mRNA that was observed in the placental biopsies of normal pregnancy and preeclampsia. Under normoxic conditions the Flt-1 and sFlt-1 mRNA levels in the explants were 3.11+/-0.6 fold in normal pregnancy and 3.6+/-0.4 fold in women with preeclampsia (p = NS by ANOVA). However, the same villous explants showed hypoxic induction of Flt-1 mRNA (NP 3.96+/-0.4 fold, p = NS and PE 5.24+/-0.6 fold, p < 0.05 by ANOVA). We analyzed Flt-1 and sFlt-1 protein levels in the peripheral blood mononuclear cells (PBMCs) to analyze the possibility of an extra-placental sFlt-1 source. Our results indicate that PBMCs of pregnant women are capable of expressing variable amounts of Flt-1 proteins. PBMCs from pregnant women exposed to hypoxia show up-regulation of HIF-1alpha and Flt-1 proteins. PBMCs obtained from women with preeclampsia (n = 9) produced significantly higher amounts of sFlt-1 under normal tissue culture conditions (104.6+/-14.3 pg/ml vs. 46.23+/-5.03 pg/ml, p < 0.05 by ANOVA) and much higher concentrations under hypoxia (196.74+/-26.3pg/ml vs. 83.3+/-13.6pg/ml, p < 0.05 by ANOVA) than PBMCs from normal pregnant women (n = 11). Moreover, analysis of PBMCs from a different group of women with a history of preeclampsia showed persistent abnormality of Flt-1 women one year post-partum. The present study indicates that Flt-1 dysregulation in PBMCs of pregnant women resulting in over-expression of sFlt-1 could be an additional (extra-placental) source of sFlt-1 that contributes to the pathogenesis of preeclampsia.     

Maternal plasma levels of cytokines in normal and preeclamptic pregnancies and their relationship with diastolic blood pressure and fibronectin levels

BACKGROUND: To determine the plasma concentrations of placental growth factor (PLGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), soluble tumor necrosis factor alpha receptor (sTNFp55), interleukin-2 receptor (IL-2R), and interleukins 6 and 10 (IL-6, IL-10) in normotensive and preeclamptic women, and to evaluate the correlations between these cytokines and the diastolic blood pressure and fibronectin levels. METHODS: A prospective case-control study. Thirty-five women with preeclampsia were compared with 34 healthy women with uncomplicated pregnancies. Peripheral venous blood samples were obtained and plasma levels of PLGF, VEGF, TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 were measured by an enzyme-linked immunoassay and fibronectin by a radial immundiffusion technic. RESULTS: In preeclampsia PLGF and VEGF levels were significantly lower, and TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 levels were significantly higher than in normotensive pregnancy (p < 0.001). The plasma levels of PLGF and VEGF significantly decreased, whereas TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 levels significantly increased with the increments in diastolic blood pressure and fibronectin levels (p < 0.001). CONCLUSIONS: Altered concentrations of various cytokines might explain the shallow placentation and endothelial cell dysfunction described in preeclampsia. The clinical severity of preeclampsia seems to correlate with the severity of the cytokine abnormalities.     

The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients

Interleukin (IL)-18 acts in synergy with IL-12 to promote development of T helper 1 (Th1) responses. On the other hand, IL-18 alone has the capacity to induce Th2 responses. Here, we have measured IL-18 and IL-12 secretion by non-stimulated peripheral blood mononuclear cells (PBMC) from 17 non-pregnant women, 21 healthy pregnant women, 9 mildly pre-eclamptic patients and 15 severely pre-eclamptic patients. Th1/Th2 ratios in PBMC were determined by flow cytometry. PBMC from healthy pregnant subjects secreted more IL-18 and less IL-12 than non-pregnant women. PBMC from severely pre-eclamptic patients secreted more IL-12 than those from healthy pregnant women, while IL-18 secretion in mildly pre-eclamptic patients resembled that in normal pregnancy. The ratios of IL-18 to IL-12 were significantly higher in healthy pregnant women than non-pregnant women. These ratios were significantly lower in severely pre-eclamptic cases than in normal pregnancy subjects, while these ratios in mild pre-eclampsia resembled those in normal pregnancy. Interestingly, Th1/Th2 ratios were negatively correlated with the ratios of IL-18/IL-12. These results suggest that elevated IL-18 secretion and decreased IL-12 secretion by PBMC may induce Th2 dominance in normal pregnancy, while elevated secretion of both IL-18 and IL-12 by PBMC may cause Th1 dominance in severe pre-eclampsia.     

The influence of paternal lymphocyte immunization on the balance of Th1/Th2 type reactivity in women with unexplained recurrent spontaneous abortion

OBJECTIVES: Paternal lymphocyte immunization has been proposed as an efficient treatment for unexplained recurrent spontaneous abortion (RSA), however precise mechanism that underlie the benefits of this immunotherapy are still unclear. It was proposed that successful pregnancy is reminiscent of T helper 2 (Th2)--dominant situation but unsuccessful pregnancy is a Th1-type situation. The aim of the study was the evaluation of influence of paternal lymphocyte immunization on the balance of Th1/Th2--type reactivity in women with unexplained recurrent spontaneous abortion. MATERIAL AND METHODS: 8 patients with a history of 3 or more consecutive primary spontaneous abortions of unknown etiology and no positive autoimmune factors were selected for the study. Immunization with paternal lymphocytes, obtained from 100 ml of peripheral blood, was performed twice prior conception with a 4-week interval. The following immunological parameters were studied: peripheral blood T lymphocyte subpopulations (CD3, CD4, CD8) and secretion of the Th1-type cytokines (IL-2, IFN-gamma), Th2-type cytokines (IL-6) and TGF-beta 1 by phytohaemaglutinin-stimulated peripheral blood lymphocytes. Evaluation of immunity parameters were performed before and 2 weeks after immunotherapy. RESULTS: It was found that paternal lymphocytes immunization significantly increase the percentage of CD4 T lymphocytes (37.11 +/- 7.65 vs. 41.38 +/- 5.57, p = 0.007). Immunotherapy also leads to a significant enhancement in Th2-type cytokines (IL-6) secretion (22,677 +/- 17,907 mg/ml vs. 44,550 +/- 15,907 mg/ml, p = 0.008) and a significant decreasing in Th1-type cytokines (IL-2) secretion (6.50 +/- 5.98 mg/ml vs. 0.00 +/- 0.00 mg/ml, p = 0.0179). CONCLUSIONS: The data of the present studies suggest that paternal lymphocytes immunization modulate of immunity in women with unexplained recurrent spontaneous abortion. Our studies indicate a shift in the balance fo cytokine profiles away from Th1-type reactivity to a Th2-type reactivity after immunotherapy.     

The circadian rhythm of blood pressure during pregnancy

OBJECTIVE: To review the literature on the circadian rhythm of blood pressure during pregnancy. DATA SOURCES: Computerized searches on MEDLINE, CINAHL, and MIRLYN. STUDY SELECTION: Selected studies from 1 969 to 1997 were evaluated. DATA EXTRACTION: Data were extracted and information was organized under the following areas: definition of and the interconnection between circadian rhythm and blood pressure; the circadian variability of blood pressure throughout the trimesters; the patterns of the circadian rhythm of blood pressure in pregnancies defined as normal and those complicated by chronic hypertension and preeclampsia; and clinical implications. DATA SYNTHESIS: The circadian rhythm of blood pressure in pregnancy is the same as in the non-pregnant state, with a nocturnal decrease, especially during sleep. In patients with chronic hypertension, the nocturnal fall in blood pressure may be steeper. Patients with mild preeclampsia may experience a less pronounced nocturnal decrease in blood pressure. Patients with severe preeclampsia may display a reversed circadian rhythm, with no decrease and/or an increase in nocturnal blood pressure. CONCLUSIONS: The patterns of the circadian rhythm of blood pressure during normal pregnancy and pregnancies complicated by chronic hypertension and preeclampsia warrant consideration when monitoring patients and implementing management plans.     

血清可溶性血管内皮生长因子受体与子痫前期发病的关系

目的探讨血清中可溶性血管内皮生长因子受体1(sFlt-1)的变化及其与子痫前期发病的关系。方法(1)应用半定量RT-PCR技术检测10例重度子痫前期患者(子痫前期组)及10例足月正常妊娠妇女(正常妊娠组)的胎盘组织中sFlt-1mRNA表达水平。(2)应用酶联免疫吸附试验(ELISA)法测定35例重度子痫前期患者(子痫前期1组)及35例正常足月妊娠妇女(正常妊娠1组)外周血中sFlt-1水平。(3)ELISA测定20例重度子痫前期患者(子痫前期2组)及20例正常足月妊娠妇女(正常妊娠2组)胎盘附着处子宫静脉血中sFlt-1水平。(4)ELISA测定10例早孕(早孕组)及10例中孕(中孕组)妇女外周血中sFlt-1水平。结果(1)子痫前期组胎盘组织中sFlt-1mRNA表达水平为0.95±0.04,明显高于正常妊娠组的0.64±0.15,两组比较,差异有统计学意义(P<0.01)。(2)子痫前期1组孕妇外周血清中sFlt-1水平为(5640±3191)ng/L,明显高于正常妊娠1组的(2194±635)ng/L,两组比较,差异有统计学意义(P<0.01)。(3)子痫前期2组孕妇子宫静脉血清中sFlt-1水平为(7673±2296)ng/L,明显高于正常妊娠2组的(3057±785)ng/L,两组比较,差异有统计学意义(P<0.01)。(4)早、中孕组孕妇外周血清中sFlt-1水平分别为(32±20)ng/L及(994±302)ng/L。结论(1)子痫前期患者外周血中sFlt-1水平明显增高;(2)血清中sFlt-1水平随孕周增加而升高,并可能与子痫前期的发病有关。     

原因不明复发性流产患者巨噬细胞表面TSP1、CD36、CD47的表达及其细胞因子的分泌

目的:探讨巨噬细胞表面分子凝血酶敏感蛋白1(TSP1)、CD36、CD47及其分泌细胞因子IL-10和IFN-γ与原因不明复发性流产发病的关系。方法:采用流式细胞技术检测10例原因不明复发性流产患者和20例正常早孕妇女外周血及蜕膜巨噬细胞表面TSP1、CD36、CD47的表达;同时用ELISPOT法检测两组外周血及蜕膜分泌IL-10和IFN-γ的巨噬细胞数。结果:原因不明复发性流产患者外周血巨噬细胞TSP1、CD36、CD47表达水平及其分泌IL-10和IFN-γ的细胞数与正常早孕妇女均无统计学差异。与正常早孕妇女比较,原因不明复发性流产患者蜕膜巨噬细胞CD36表达水平明显升高(P<0.01),TSP1表达水平明显降低(P<0.01),CD47表达水平无明显差异(P>0.05)。蜕膜组织分泌IL-10的巨噬细胞数显著降低(P<0.05),而分泌IFN-γ的巨噬细胞数量无明显差异。结论:蜕膜巨噬细胞在维持正常妊娠免疫耐受和导致原因不明复发性流产发病中起重要作用。     

Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado.

OBJECTIVE: Our purpose was to determine the case incidences of preeclampsia at low and high altitudes and whether maternal blood pressure course during pregnancy differs between low and high altitudes. STUDY DESIGN: This was a retrospective cohort study of pregnancies in sociodemographically matched communities at low and high altitudes in Colorado; each community had a small hospital served by family practitioners and was located >100 miles from major urban areas. Included were consecutive singleton pregnancies of women without chronic disease that resulted in live-born infants at >28 weeks' gestation during an 18-month period (n = 116 at 1260 m, n = 93 at 3100 m). Clinic and hospital medical records were searched and data pertaining to hypertensive complications of pregnancy and serial blood pressure measurements were abstracted. RESULTS: Despite similar maternal risk factors, the case incidences of preeclampsia were 16% at 3100 m and 3% at 1260 m. As in sea-level pregnancies, mean blood pressure fell until week 20 in normotensive pregnancy at 1260 m. Mean pressure rose linearly, however, in normotensive women at 3100 m and in women with preeclampsia at both 1260 m and 3100 m. High altitude acted independently of known risk factors and yielded an odds ratio for preeclampsia of 3.6 (95% confidence interval 1. 1-11.9). Birth weight was 285 g lower at 3100 m despite similar gestational ages. CONCLUSION: The normal pregnancy-associated fall in blood pressure was absent at 3100 m, even in women who remained normotensive. The incidence of preeclampsia was increased at high altitude. Residence at high altitude interferes with the normal vascular adjustments to pregnancy, increasing the incidence of preeclampsia, and is perhaps analogous to other conditions that decrease uteroplacental oxygen delivery.     

Placental imbalance of Th1- and Th2-type cytokines in preeclampsia

OBJECTIVES: To characterize the changes in the level of T helper 1 (Th1)- [interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha] and Th2-type cytokine (IL-10) and the ratios of Th1/Th2 (IL-2/IL-10 and TNF-alpha/IL-10) in placentae from women with preeclampsia and women with gestational hypertension. METHODS: Placental levels of IL-2, TNF-alpha, and IL-10 were determined with radioimmunoassay and Th1/Th2 ratios (IL-2/IL-10 and TNF-alpha/IL-10) calculated in the placentae from 22 women with preeclampsia, 15 women with gestational hypertension, and 32 normal term pregnant women. RESULTS: Although preeclampsia had the trend of the increase in the placental levels of IL-2 and TNF-alpha and the trend of the decrease in placental IL-10, there were not significant difference in placental levels of IL-2, IL-10, and TNF-alpha among preeclampsia, gestational hypertension, and normal pregnancy (P > 0.05 for all). Placental ratios of IL-2/IL-10 and TNF-alpha/IL-10 were significantly higher in preeclampsia than in normal pregnancy (P = 0.035 and P = 0.005, respectively). No differences of Th1/Th2 ratios were found between preeclampsia and gestational hypertension and between gestational hypertension and normal pregnancy (P > 0.05 for all). CONCLUSIONS: Alterations of placental balances of cytokines with Th1 predominance were demonstrated in preeclampsia. These associations may offer insights into the pathogenesis of preeclampsia.     

Lipid-soluble antioxidants and pregnancy: maternal serum levels of coenzyme Q10, alpha-tocopherol and gamma-tocopherol in preeclampsia and normal pregnancy

It has been hypothesized that in preeclampsia, the antioxidant-deficient state may facilitate increased attacks of free radicals, which may result in endothelial cell damage. The purpose of this study was to investigate the association of three lipid-soluble antioxidants, coenzyme Q10, alpha-tocopherol and gamma-tocopherol, with preeclampsia and normal pregnancy. Serum levels of all three antioxidants in 42 women with normal pregnancies, 25 with mild preeclampsia and 28 with severe preeclampsia were measured by high-pressure liquid chromatography. A significant decrease was observed in serum levels of coenzyme Q10 and alpha-tocopherol (p < 0.001 for each by the Kruskal-Wallis rank test) in women with preeclampsia compared to levels in normal pregnancy. gamma-Tocopherol levels were comparable among the different groups. Logistic regression analysis revealed significant association between grades of preeclampsia and both serum coenzyme Q10 and alpha-tocopherol levels (p = 0.000 and 0.030, respectively). Coenzyme Q10 and alpha-tocopherol are potent antioxidants, and the decreased levels of these two antioxidants in preeclampsia may alter the normal redox balance, thereby reducing the ability of antioxidant defenses to protect against free radical damage. This could be a factor in the endothelial cell damage observed in preeclampsia.     

Expression of the molecules HLA-G and HLA-E modulates cytokine production of monocyte generated dendritic cells

OBJECTIVE: Preferential secretion of Th1-like cytokine is mainly a property of monocyte derived dendritic cells (DC). Since normal early pregnancy is characterized by a shift towards a Th2-like cytokine pattern, it may be assumed that cytokine secretion by DC during early pregnancy could be modulated by the non-classical HLA molecules G and E present on invasive trophoblast. MATERIAL AND METHODS: DC were cultivated from monocytes isolated from peripheral blood mononuclear cells. DC were cocultured with K-562 leukemia cells lacking the class I and II HLA antigens transfected with either HLA-G or HLA-E or ultratransfected cells (controls) and the concentrations of IL-8, IL-10, IL-12p70, IL-18 and TNF-alpha were measured in the supernatants by ELISA. RESULTS: Coculture with ultratransfected cells resulted in a significant increase of the production of IL-8 and TNF-alpha by mature and immature DC and of IL-10 by immature DC (p < 0.01). When cocultured with HLA-G and HLA-E transfected K-562 cells, the secretion of IL-8 by immature and mature DC and that of IL-10 and TNF-alpha by immature DC was significantly (p < 0.01) decreased. The contact with HLA-G and HLA-E transfected cells had no effect on the production of IL-12p70 and IL-18 by DC. CONCLUSIONS: These results show that DC react with an increased cytokine release upon contact with cells lacking HLA class I and II antigens. The suppressive effect of HLA-G and HLA-E on the secretion of TNF-alpha (Th1 cytokine), IL-10 (Th2 cytokine) and IL-8 (chemokine) by immature DC could be interpreted as further evidence for the central immunotolerance role of HLA-G and HLA-E during early pregnancy.     

Examination of maternal plasma erythropoietin and activin A concentrations with regard to circulatory erythroblast levels in normal and preeclamptic pregnancies

OBJECTIVES: Preeclampsia has been shown to be associated with an increased number of fetal and maternal erythroblasts in the maternal circulation, suggesting that preeclampsia involves increased leakage of fetal cells across the placental barrier, as well as increased erythropoiesis. We examined the relationship between circulatory erythroblast levels with maternal plasma concentrations of erythropoietin and activin A. METHODS: In a case-control study, we examined 15 pregnancies affected by preeclampsia and 10 matched controls. Erythroblasts were enriched from maternal blood samples by magnetic cell sorting, enumerated and correlated with corresponding plasma activin A and erythropoietin concentrations. RESULTS: The proportion of erythroblast was elevated in preeclampsia (0.8 vs. 0.1%, p = 0.023). Erythropoietin and activin A concentrations were significantly elevated in preeclampsia (100.4 vs. 44.5 pg/ml, p = 0.023, and 7.4 vs. 1.85 ng/ml, p = 0.029, respectively). Circulatory erythroblast numbers were found to correlate with plasma activin A concentrations (r = 0.76, p = 0.01) in cases with preeclampsia. No such relationship existed for erythropoietin. CONCLUSIONS: Our data suggest that increased concentrations of activin A promote enhanced levels of erythropoiesis in preeclampsia. As the placenta is one of the major sources of activin A in pregnancy, this increase in activin A-dependent erythropoiesis in preeclampsia may be a reflection of an underlying placental hypoxic condition.     

Anti-hypertensive drugs alter cytokine production from preeclamptic placentas and peripheral blood mononuclear cells.

OBJECTIVE: Antihypertensive drugs are administered to women with preeclampsia to control blood pressure and fluid overload. Whether they modulate placental or circulating cytokine production in women with preeclampsia is unknown. This study examines the effect of pharmacological doses of antihypertensive drugs on the production of IL-10, tumor necrosis factor alpha (TNF-alpha), and IL-6 in placental tissue and peripheral blood mononuclear cells (PBMCs) from women with preeclampsia. METHODS: Term placenta samples (n = 6) and PBMCs from whole blood (n = 6) were obtained from women with preeclampsia. Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs (clonidine, diazoxide, hydralazine, and furosemide). The dose effect of drugs on the production of placental and circulating cytokines IL-10, TNF-alpha, and IL-6 was examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data suggest that clonidine can stimulate anti-inflammatory IL-10 production from PBMC while decreasing pro-inflammatory TNF-alpha, whereas low doses of hydralazine increased the production of IL-10, TNF-alpha, and IL-6 from preeclamptic PBMCs. There was a reduction in IL-10, TNF-alpha, and IL-6 production with increasing doses of clonidine and hydralazine by placentas in preeclampsia. IL-10, TNF-alpha, and IL-6 production from preeclamptic placenta and PBMCs were inhibited by diazoxide and furosemide. CONCLUSIONS: Antihypertensive drugs may alter Th1/Th2 cytokine balance in preeclamptic tissues in vitro.     

Cytokine expression in peripheral blood lymphocytes indicates a switch to T(HELPER) cells in patients with preeclampsia

We sought to determine whether cytokine expression in peripheral blood mononuclear cells is altered in patients with preeclampsia and in patients with a history of recurrent spontaneous abortion (RSA). Twenty-four patients with preeclampsia and twenty patients with a history of RSA were included into the study. Two control groups consisted of twenty healthy pregnant and twenty healthy non-pregnant women. The intracellular expression of interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were determined in peripheral blood mononuclear cells (PBMCs) by flow cytometry as a measure of cytokine production. IL-2 synthesis was significantly elevated in the third trimester in preeclamptic patients in comparison with the control group. Non-pregnant women with RSA showed a significantly lower expression of IFN-gamma compared to the non-pregnant control group. Our data suggest an abnormal immune response in preeclamptic patients characterised by a shift to a predominantly Th1-type immunity.