Increased expression of interleukin-1 beta is associated with persistence of the disease and invasion in complete hydatidiform moles (CHM)

Complete hydatidiform moles (CHM), a post-conceptual pathologic condition of the placenta, have a high prevalence rate (12/1,000 deliveries) in Kerala, India. This study addresses the expression of IL-1 alpha and beta by immunohistochemistry in relation to persistence and invasion of the disease. Mild to moderate expression of IL-1 alpha in the villous cytotrophoblasts, syncytiotrophoblasts and decidua of the first trimester in the normal placenta and all gestational ages in the molar placenta were observed. IL-1 beta expression was observed in the extravillous trophoblasts, syncytiotrophoblasts and decidua in both the normal and molar placentae and also in the villous cytotrophoblasts and the stromal Haufbaur cells in molar placentae. Strong expression of IL-1 beta in the placenta suggests its involvement in placental physiology supporting earlier reports. Higher expression of IL-1 beta correlated well with the invasive and persistent nature of the tumour and holds potential as a marker of persistence and invasion in CHM.     

ICAM-1 is overexpressed by villous trophoblasts in placentitis

Although an in vitro study has hypothesized that expression of ICAM-1 by villous trophoblasts could be important for the influx of maternal immune cells in villitis, it remains to be shown whether the same phenomenon occurs in human villitis. To investigate the expression of ICAM-1 by villous trophoblasts, its relationship with rupture of the trophoblastic barrier and influx of immune cells into the villi, we analysed 18 paraffin-embedded placentas with placentitis (5 by Toxoplasma gondii, 3 by Trypanosoma cruzi, 2 by Paracoccidioides brasiliensis and 8 of unknown aetiology - VUE) and 8 control placentas for detection of ICAM-1 by immunohistochemistry. All cases but one of placentitis showed trophoblast overexpression of ICAM-1 in the inflamed villi, located almost exclusively next to the areas of trophoblastic rupture. The villitis cases (caused by T. cruzi, T. gondii and VUE) presented leukocyte adherence in the areas of trophoblastic rupture. When the inflammatory reaction was situated in the intervillous space (placentitis by P. brasiliensis), in spite of the trophoblastic rupture and ICAM-1 overexpression there was no leukocyte influx into villi. None of the control placentas showed ICAM-1 expression by the trophoblast. We concluded that overexpression of ICAM-1 by villous trophoblasts occurs during placentitis characterized by accumulation of leukocytes in the villous or intervillous space and probably plays an important role in the rupture of the trophoblastic barrier. The influx of immune cells into the villi appears to be mediated by ICAM-1 but the location of the antigen within villous stroma is certainly a crucial factor for its occurrence.     

Less HLA-G expression in Plasmodium falciparum-infected third trimester placentas is associated with more natural killer cells

During pregnancy, maternal immune tolerance of the fetal semi-allogeneic graft is partly the consequence of extravillous trophoblast HLA-G expression and its interaction with natural killer (NK) cells. Plasmodium falciparum malaria is frequently associated with maternal and fetal complications. Local HLA-G expression and the number of NK cells were evaluated immunohistochemically in P. falciparum-infected and uninfected placentas (15 each) collected in a seasonal malaria-hypoendemic area. In control placentas, HLA-G was almost always expressed in extravillous trophoblast whereas, in infected placentas, it was significantly more weakly expressed in extravillous trophoblast but was also detected in intervillous space macrophages. NK cells were evaluated in intervillous and intravillous spaces and in basal plate. NK cells were always more abundant in basal plate than in intervillous and intravillous spaces in infected or control placentas. For each area, more NK cells were seen in infected than control placentas. These data suggest that HLA-G down-regulation and more NK cells in placentas may be among the mechanisms involved in poor birth outcome associated with P. falciparum infection.     

Molecular interactions in the placenta during malaria infection

Placental malaria is the placental sequestration of Plasmodium falciparum infected erythrocytes that accumulate in the intervillous space, resulting in pathological alterations. The intervillous space, the main compartment for exchange of nutrients and delivery of oxygen to the fetus, is of utmost importance for fetal development. Events leading to adverse outcomes of placental malaria can be summarized in four steps: (1) accumulation of P. falciparum infected erythrocytes; (2) infiltration of monocytes and macrophages; (3) alteration of the placental cytokine balance and (4) pathogenesis of adverse pregnancy outcomes. These events are triggered by chemokines and cytokines leading to impaired materno-fetal exchange and damage to the placenta.This review describes the events during placental malaria infection at molecular level and presents a simplified model describing all crucial steps leading to adverse pregnancy outcomes based on a review of recent literature (August 2009).     

Intercellular adhesion molecule-1 expression in massive chronic intervillositis: Implications for the invasion of maternal cells into fetal tissues

Introduction

Massive chronic intervillositis (MCI), also known as chronic intervillositis of unknown etiology, is a placental lesion associated with massive infiltration of mononuclear cells in the intervillous space, poor perinatal outcome, and high rate of recurrence. Our previous demonstration of increased syncytiotrophoblast (st) intercellular adhesion molecule-1 (ICAM-1) expression in villitis lesions and the finding of extensive monocyte/macrophagic cells in the maternal intervillous space in MCI, led us to further investigate stICAM-1 in MCI.

Materials and methods

A cross-sectional study of placentas from the third trimester of pregnancy (34–41 weeks gestation) was conducted to determine stICAM-1 in MCI (n = 7). MCI stICAM-1 expression was compared to stICAM-1 in villitis (n = 7) and in normal villi from placentas with (n = 7) and without (n = 7) villitis. Maternal cells within villi in MCI were identified in placentas mismatched for maternal/fetal human leukocyte antigen (HLA)-DRw52. Villitis was diagnosed with hematoxylin and eosin staining and antibody to CD3 in serial sections, and ICAM-1 in syncytiotrophoblasts was confirmed with antibodies to ICAM-1 and cytokeratin.

Results

Placentas with MCI had higher stICAM-1 (79.8%) than placentas with villitis (27.1%), normal villi from placentas with villitis (11.5%), and normal villi from placentas without villitis (0.3%). Maternal cells were identified within villi of placentas (n = 5) mismatched (mothers positive, fetuses negative) for HLA-DRw52.

Conclusions

Placentas with MCI have more stICAM-1 than placentas with or without villitis lacking MCI. The finding that MCI and villitis have prominent stICAM-1 and maternal cells in the villi suggests that MCI and villitis could have a similar pathophysiologic mechanism.     

Syncytiotrophoblast degradation and the pathophysiology of the malaria-infected placenta

Malaria is associated with excessive parasitic infection of the placenta and a reduction in neonatal birthweight. This study has investigated placental cell death in women with active and past malarial infection. Term placentae, with and without malarial pathology, were obtained from women in The Gambia. Active and past malaria infections were identified in placental sections and histological examination was used to determine the number of villi, the incidence of apoptosis, syncytial degradation, fibrinoid deposition and the frequency of syncytial knots. Placentae with active malaria infection showed erythrocyte adhesion of infected cells to syncytiotrophoblast, syncytial degradation, increased syncytial knotting and, in rare cases, localized destruction of the villi. Past malarial infection was characterized by syncytiotrophoblast disruption and fibrin-type fibrinoid (FTF) deposition. Perivillous FTF deposition was consistent with increased syncytial lesions and both increased lesions and syncytial knots were associated with birthweight reductions. Active malaria infection produced no alteration in placental apoptosis. The numbers of chorionic villi remained unchanged and infiltration of inflammatory cells, although not measured directly, appeared to be non-pervasive within the infected tissue. These observations establish a direct link between malaria parasitic infection and syncytiotrophoblast damage. The placental rejection of parasite-affected syncytia may invoke structural changes to compensate for inadequate placental exchange. Syncytial destruction could have serious implications; impairing fetal growth and in some rare cases, providing a previously unrecognized pathway to congenital infection.     

Immunohistochemical study of annexin V expression in placentae of preeclampsia

We investigated the clinical significance of annexin V in the placentae with preeclampsia and found: (1) annexin V was detected on trophoblasts in the placentae and the staining intensity of annexin V in the placentae from such patients was reduced when compared to normal placentae; (2) as expression of annexin V was reduced, the gestosis index from patients with preeclampsia was elevated and the standard deviation value in the infant's standard weight was decreased; plasma level of the fibrin degradation products and thrombin-antithrombin III complex from patients were elevated as the expression of anexin V was reduced. These results suggest that the reduced expression of annexin V in the placentae from patients with preeclampsia may lead to a hypercoagulable state in the intervillous space and may be associated with the development of intrauterine growth restriction.     

Labour-associated expression of intercellular adhesion molecule-1 (ICAM-1) in placental endothelial cells indicates participation of immunological processes in parturition.

Inflammatory cytokines induce or upregulate de novo expression of cell adhesion molecules on endothelial and epithelial cells. In order to demonstrate inflammatory reactions within placental tissues in association with normal term as well as non-infection-induced preterm labour, the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) was examined by immunohistochemical methods in both trophoblastic villi (n=123) and umbilical cord (n=61). As a result, ICAM-1 immunoreactivity was exclusively localized in the endothelial cells of the fetal vascular system, while VCAM-1 and ELAM-1 were not detected. Whereas ICAM-1 was not expressed in early pregnancy (9-12 weeks of gestation), it could be weakly detected at the end of pregnancy in cases of elective caesarean delivery in the absence of labour, and was significantly more strongly expressed in cases of vaginal delivery after spontaneous onset of normal term labour. Significantly increased immunoreactivity of ICAM-1 within umbilical cord tissues was also found in association with uncontrollable preterm labour in the absence of intrauterine infection which was excluded after histological examination of fetal membranes, umbilical cord and chorionic plate. We conclude that ICAM-1 expression in the endothelium of the fetal vascular system is associated with the presence of labour and reflects participation of immune-inflammatory reactions in labour-promoting mechanisms.     

Placental pathology in midtrimester pregnancies interrupted by intra-amniotic injection of hypertonic urea.

The histological appearances of 52 placentae from patients who had a urea-induced second trimester abortion were studied. Extensive subchorionic intervillous fibrin deposition and swollen degenerated stromal cells (probably Hofbauer cells), were found both in the placenta and membranes. Between urea injection and abortion, serial vaginal smears showed signs of progesterone deficiency. The urea-induced placental and fetal damage was similar to that seen with hypertonic saline.     

Perfusion with lipopolysaccharide differently affects the secretion of interleukin-1 beta and interleukin-1 receptor antagonist by term and preterm human placentae

The aim of the present study was to examine the effect of lipopolysaccharide (LPS) on the secretion of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) and of its natural inhibitor interleukin-1 receptor antagonist (IL-1Ra), by perfused human term and preterm placental tissue. Eight term and eight preterm placentae were collected immediately after delivery; four term and four preterm placentae were perfused with control medium (without LPS) and the other four term and four preterm placentae were perfused with medium containing LPS. The release of IL-1beta into the maternal compartment by term placenta was significantly higher than the release by preterm placenta (p<0.001). However, there were no significant differences between IL-1beta levels released into the fetal compartments of term and preterm placentae. No significant differences were observed in the release of IL-1Ra into the maternal and fetal compartments of term placenta, when compared to preterm placenta. Exposure to LPS significantly decreased the capacity of term placenta to release IL-1beta into the maternal compartment (p<0.001) and increased the capacity of term placenta to release IL-1Ra into the maternal and fetal compartments (p<0.001 and p=0.017, respectively). However, the capacity of preterm placentae to release IL-1beta and IL-Ra into the maternal and fetal compartments was not affected by LPS. IL-1beta was expressed by both term and preterm placentae before and after perfusion (+/- LPS), by epithelial cells of the amnion, chorion, by syncytiotrophoblast and stromal cells of villous tissue and by the decidua. IL-1Ra in term and preterm placentae was expressed before perfusion mainly in epithelial cells of the amnion. After perfusion of term placentae (+/- LPS), additional IL-1Ra expression was seen in epithelial cells of the amnion and in syncytiotrophoblast and stromal cells of villous tissue and by the decidua. However, perfusion of preterm placentae (+/- LPS) did not affect IL-1Ra expression. The localization of IL-1beta and IL-1Ra in both term and preterm human placental tissue suggests a their physiologic role. The data presented indicates that the IL-1 system in term and preterm placentae seems to be differently affected by LPS. Down-regulation in the release of the pro-inflammatory cytokine IL-1beta and the up-regulation of its antagonist (IL-1Ra) may be a part of the inflammatory response to infection in human term, but not preterm, placentae. The IL-1 system in term and preterm placentae seems to be differently affected by LPS.     

Expression and localization of cell adhesion molecules in human fetal membranes during parturition

There is increasing evidence to support the view that human parturition represents an inflammatory process. We have previously demonstrated that parturition is associated with leukocyte invasion and pro-inflammatory cytokine production in the cervix and myometrium. Furthermore, we have shown that several cell adhesion molecules are upregulated in these tissues during labor. In fetal membranes, previous studies have shown intercellular adhesion molecule-1 (ICAM-1) upregulation in association with labor. The role of other adhesion molecules has not been explored. The aims of this study were, therefore, to determine the expression of ICAM-1, platelet endothelial cell adhesion molecule (PECAM), vascular cell adhesion molecule (VCAM) and E-selectin in pre- and post-laboring amnion and choriodecidua and to identify cell types responsible for their expression. Biopsies of fetal membranes were obtained from pregnant women delivered by caesarean section before the onset of labor (n = 8) and following spontaneous vaginal delivery (n = 8). Cell adhesion molecules were identified using immunohistochemistry and messenger RNA expression quantified using Northern analysis. We found that following labor, ICAM-1 mRNA expression was significantly upregulated in amnion and choriodecidua (P < 0.05). PECAM mRNA expression was also increased in choriodecidua (P < 0.05). The main cell types responsible for adhesion molecule expression were leukocytes, amniotic epithelial cells and endothelial cells. The upregulation of ICAM-1 and PECAM mRNA expression in fetal membranes following labor provides further evidence that fetal membranes play an important role in the inflammatory process of parturition.     

Fibrin-type fibrinoid in placentae from pregnancies associated with maternal smoking: association with villous trophoblast and impact on intervillous porosity

Smoking during pregnancy perturbs maternal haemostasis via activated coagulation which could include greater coagulation (fibrin-type fibrinoid deposition) in the placental intervillous space. This might affect intervillous haemodynamics and transport of oxygen and nutrients to the fetus. Fibrin deposits could influence the sizes and numbers of intervillous spaces ('pores') and perivillous fibrin could reflect changes in the nature or activity of trophoblast. Here, we test whether or not smoking is associated with differences in the composition of villous trophoblast, the amounts and patterns of fibrin and, hence, the dimensions and numbers of intervillous pores. Random samples of placentae were taken from pregnancies classified according to smoking status (non-smokers, light smokers, heavy smokers). Stereology was used to estimate volumes of intervillous space and fibrin, test for differences in trophoblast composition and patterns of fibrin deposition at the villous surface, and determine the impact of deposits on the mean volumes and theoretical numbers of intervillous pores. No group differences were found in total volumes or surfaces of trophoblast or total volume of intervillous fibrin. However, the total surfaces of syncytial knots declined in smokers and the surfaces of syncytial bridges increased. Particularly in heavy smokers, this was associated with reduced deposits of perivillous fibrin at syncytial knots. In all placentae, the greatest deposits occurred where there was trophoblast denudation. Little fibrin was seen on thin regions of syncytium. Regardless of smoking status, intervillous fibrin reduced intervillous pore size and increased pore number. However, heavy smokers had larger pores. Reductions in syncytial knots are consistent with reports that smoking reduces the incidence of trophoblast apoptosis whilst increases in syncytial bridges are consistent with enhanced branching angiogenesis. Results confirm that perivillous fibrin accumulates preferentially at denudation sites. They also suggest that smoking perturbs the normal pattern of fibrin deposition, that the impact is greater in heavy smokers and that the placental site is privileged or active in terms of fibrinolytic or anti-coagulatory activity. This activity seems to reside in thin regions of syncytium.     

Heme oxygenase expression in cultured human trophoblast cells during in vitro differentiation: effects of hypoxia

Heme oxygenases (HO-1 and HO-2) are responsible for the production of carbon monoxide, a vasodilator. HO is important in controlling placental blood flow and expression can be sensitive to oxygen. We previously reported a reduction in HO-2 expression in placentae obtained from patients with pre-eclampsia or living at high altitude, both associated with placental hypoxia. Thus we hypothesized that HO expression in cultured trophoblasts would be altered by exposure to hypoxia. HO-1 and HO-2 expression was assessed in trophoblast cell cultures following exposure to different oxygen environments. Western blot analyses showed that HO-1 expression in syncytiotrophoblast was significantly lower than in cytotrophoblasts in standard conditions (p < 0.05). There was no difference in HO-1 expression in cytotrophoblasts transferred to 2% O2 for various times. However, exposure of syncytiotrophoblast cultures to hypoxia for 12 h resulted in a significant reduction in HO-1 expression (p < 0.05). HO-2 expression was not affected by exposure to hypoxia in either cytotrophoblast or syncytiotrophoblast cultures. Possible interpretations of these findings are that chronic hypoxia alone is not responsible for reduced HO-2 expression or a much longer exposure to chronic hypoxia (perhaps months) is required. This study also reinforces the complexities of HO regulation by oxygen.     

Effect of activin A on tumor necrosis factor-alpha/intercellular adhesion molecule-1 pathway in endometrial stromal cells

OBJECTIVE[S]: Activin A and inhibin A are growth factors expressed by human endometrium involved in the control of endometrial functions. In the present study we investigated the effects of activin A and inhibin A in modulating the tumor necrosis factor (TNF)-alpha/intercellular adhesion molecule (ICAM)-1 system in cultured human endometrial stromal cells. STUDY DESIGN: Endometrial samples were obtained from 34 reproductive age women undergoing laparoscopy for benign ovarian cysts or infertility. Endometrial stromal cells were cultured and soluble ICAM-1 and TNF-alpha were measured in cell-free supernatants following treatment with or without activin A or inhibin A. Cell surface ICAM-1 was assayed by flow cytometry by staining endometrial cells with specific monoclonal antibodies. RESULTS: Activin A and inhibin A did not influence either the expression of cell surface ICAM-1 or soluble ICAM-1 shedding by cultured endometrial cells. On the other hand, TNF-alpha secretion significantly increased in presence of activin A but not of inhibin A. CONCLUSIONS: Since TNF-alpha modulates several endometrial processes such as menstruation, proliferation, apoptosis, implantation and decidualization, an effect of activin A in the physiological control of endometrium is further supported by the present data.     

Caveolae and caveolin-1 in human term villous trophoblast

Caveolae are flask-shaped invaginations of the plasma membrane found in many cell types, particularly endothelium. A major structural component is the membrane protein caveolin-1 which associates with numerous signalling molecules, including endothelial nitric oxide (eNOS). Caveolin-1, which co-immunoprecipitates with eNOS in preparations from endothelial cells, regulates eNOS activity, holding it inactive. Controversy now exists regarding the presence of caveolae and caveolin-1 in trophoblasts, hence this study was carried out to examine whether the high levels of eNOS expressed in human syncytiotrophoblast are associated with caveolin-1, and to find out if caveolae are present in villous cytotrophoblasts and syncytiotrophoblast.Immunohistochemistry of term placentae revealed only weak labelling for caveolin-1 in the syncytiotrophoblast although the endothelium of the terminal villus vessels stained strongly. By electron microscopy, numerous caveolae were identified in the villus capillary endothelium but were extremely rare in the syncytium. Caveolin-1 staining was extensive in purified, isolated term villous cytotrophoblasts, with the purity of these cytokeratin positive cells confirmed by cytospin analysis and flow cytometry. Caveolae were clearly demonstrated in ultrastructural sections of the purified cytotrophoblasts. The time course of expression of caveolin-1 and eNOS during differentiation of villous cytotrophoblast into syncytiotrophoblast in culture was studied. Western analysis showed that caveolin-1 expression evident in day 1 whole cell lysates decreased at day 3 when the cells had syncytialized and declined further by day 6, while the levels of actin (control) remained high. eNOS expression in the same samples followed a different pattern, with the low levels in day 1 cells increasing substantially by 3 days in culture, subsiding again by day 6. eNOS association with caveolin-1 in day 1 and day 3 trophoblast cultures was evidenced by the demonstration that eNOS co-immunoprecipitates with caveolin-1 and vice versa. We conclude that human villous cytotrophoblasts express caveolin-1, which assembles into caveolae. Differentiation into syncytium results in a decrease, but not disappearance, of expression of caveolin-1 and a marked reduction of the caveolae.     

Enhanced expression of intercellular adhesion molecule-1 (ICAM-1) in amnion with term and preterm labour

To evaluate the association between intercellular adhesion molecule-1 (ICAM-1) in the amnion and preterm labour and delivery, we have assessed ICAM-1 mRNA abundance by Northern analysis and protein levels by enzyme-linked immunosorbent assay (ELISA), in samples of this tissue after term and preterm delivery. The median ICAM-1 mRNA expression following preterm delivery (PTD, n=30) was 24 times greater (P< 0.05) than following elective caesarean section prior to labour at term (CST, n=14). ICAM-1 expression following vaginal delivery after spontaneous labour at term (SLT, n=11) was seven times greater than in the CST group (P< 0.05). The concentration of ICAM-1 protein in the PTD samples (n=31) was four-fold greater than (P< 0.05) in CST (n=14). It was also three-fold greater than in the SLT (n=15) samples (P< 0.05). The results were substantially the same when a preterm spontaneous labour group (PTL) (n=26), exclusive of deliveries complicated by pre-eclampsia (n=1) or intrauterine growth restriction (n=3), was compared to the CST and SLT groups. The ICAM-1 mRNA expression did not differ significantly (P=0.93) between PTL with (n=12) or without (n=14) indicators of intrauterine infection. The results were similar when ICAM-1 protein concentrations were compared (P=0.43) between these two groups. These findings indicate that ICAM-1 is expressed by the human amnion and that this expression is elevated with preterm labour and delivery.     

ICAM-1 expression on immune cells in chronic villitis

IntroductionICAM-1 expression on the villous syncytiotrophoblast (ST) is believed to participate in migration of maternal cells into the inflamed villi regardless of villitis etiology. However, its expression on immune cells in chronic villitis (CV) has yet to be analyzed. ICAM-1 induces cell–cell adhesion allowing intercellular communication, T cell-mediated defense mechanism, and inflammatory response.Material and methods21 cases of CV (all without an identifiable etiologic agent) and 3 control placentas were analyzed using ICAM-1, and for immune cells CD45, CD3 and CD68. These cells were subdivided according to their location in inflamed villi: a) within the inflamed villi and b) outside forming perivillous aggregates.ResultsLarge amounts of CD45, CD3 and CD68 were found within the inflamed villi and forming perivillous aggregates attached to areas of trophoblastic loss. Inflamed villi usually showed ICAM-1+ ST. The majority of immune cells surrounding areas of trophoblastic rupture presented marked expression of ICAM-1. In contrast, a small number of immune cells within the inflamed villi exhibited ICAM-1 expression. Only some (<5%) inflamed villi without trophoblastic rupture and with ICAM-1+ ST presented adherence of immune cells.DiscussionIn inflamed villi of chronic villitis, the level of ICAM-1 expression on immune cells depends on their location: high in number of cells in the perivillous region and low within the villi. The strongest expression of ICAM-1 on immune cells attached to areas of trophoblastic rupture suggests that the loss of trophoblast can lead to an amplification of the inflammatory response.     

Normal expression of cell adhesion molecules in placentae from women with systemic lupus erythematosus and the antiphospholipid syndrome

Pregnant women with active systemic lupus erythematosus (SLE) and/or the antiphospholipid syndrome (APS) are prone to recurrent miscarriage, pre-eclampsia, intrauterine growth restriction and premature delivery. Placental dysfunction may account for these complications yet the mechanisms remain uncertain. Amongst these, an inflammatory response in the placental vasculature could play a role, involving recruitment of neutrophils and platelets and the increased endothelial expression of cell adhesion molecules (CAM), central to the recruitment process. The aim of this study was primarily to investigate CAM expression in the fetoplacental vasculature in women with SLE/APS. Circulating maternal concentrations of soluble CAM were also elucidated.There were no differences in CAM immunostaining in placentae from patients with SLE and/or APS compared with controls. In both patients and controls moderate immunostaining for the intercellular adhesion molecule-1 (ICAM-1) was observed in placental vascular endothelium and mild immunostaining was present in the placental villous stroma. Strong immunostaining for platelet endothelial CAM (PECAM) occured in the placental vascular endothelium whereas P-selectin was mildly expressed in the stem vessel endothelium only. Vascular CAM-1 (VCAM-1) and E-selectin were undetectable in either study or control placentae. In contrast, ICAM-1 and VCAM-1 but not E-selectin, as assessed by immunoassay (ELISA), were elevated in maternal serum from SLE/APS patients compared with controls. This study suggests that upregulation of CAM expression and subsequent activation of neutrophil and/or platelet activity within the placental villous tree is unlikely to be a mechanism by which the adverse pregnancy outcome arises in SLE/APS pregnancies. However, maternal endothelial cell activation (ECA) may play a more important role.     

Systemic inflammation, cellular influx and up-regulation of ovarian VCAM-1 expression in a mouse model of polycystic ovary syndrome (PCOS)

PCOS, a major cause of anovulatory sterility, is associated with obesity, insulin resistance and chronic inflammation. New evidence suggests that the immune system aggravates the clinical features of PCOS. Our aim was to study the immune, metabolic and endocrine features of a mouse model of PCOS elicited by androgenisation using dehydroepiandrosterone (DHEA). We observed a significant weight gain and insulin resistance in DHEA-androgenised mice, coupled with the formation of ovarian follicular cysts. DHEA up-regulated the expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the granulosa cell layer of the majority of cysts, and VCAM-1 expression in the theca cell layer of all follicles and cysts. The expression of these markers was low in control tissue. Peritoneal cells from PCOS-mice showed enhanced production of inflammatory cytokines, suggesting an association between chronic inflammation and PCOS. In addition, DHEA-androgenisation induced the activation of CD4(+) cells both in vivo and in vitro, and their expression of the respective ligands for VCAM-1 and ICAM-1, VLA-4 and LFA-1, as assessed in vitro. CD4(+) cells were present in androgenised ovaries, especially in the granulosa cell layer of cysts with high VCAM-1 expression. Herein, we present novel evidence that the immune system is activated systemically and locally in a mouse model for PCOS. We propose that VCAM-1 is involved in aggravating PCOS symptoms by promoting leukocyte recruitment to the ovaries and perpetuating local inflammation. These findings offer novel therapeutic opportunities for PCOS, such as blockage of VCAM-1 expression.