Biomedical subjects

Ian L Sargent

Publications and source records attributed to Ian L Sargent.

10 recordsLinked to original sources

PubMed2006

NK cells and human pregnancy--an inflammatory view.

For several years, reproductive immunology has been dominated by the 'Th1/Th2' hypothesis, in which the fetus avoids maternal T-cell rejection through a bias towards T-helper (Th)2 cytokine production. The discovery that normal pregnancy is a controlled state of inflammation, at an early stage at the implantation site and also later systemically, has challenged this concept, as has the finding that the predominant immune interactions in the decidua are between the placental trophoblast and maternal natural killer (NK) cells instead of T cells. Here, we extend this concept to the interaction between the trophoblast and NK cells in the maternal circulation. We suggest novel ways in which the trophoblast might stimulate the maternal systemic inflammatory response, and how dysfunctional NK-cell activation could result in the maternal syndrome of pre-eclampsia.

Female↗

PubMed2006

Immunoregulation in normal pregnancy and pre-eclampsia: an overview.

Pre-eclampsia is a major disorder of human pregnancy, which may have an immunological basis. It is a disease of two stages. The first stage concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The inadequate trophoblast invasion may result from decreased expression of human leukocyte antigen-G (HLA-G) leading to an abnormal interaction with decidual natural killer (NK) cells, which are believed to play a major role in these processes through the production of immunoregulatory cytokines and angiogenic factors. Recent evidence suggests that the interaction between trophoblast human leukocyte antigen-C (HLA-C) molecules and decidual NK cell receptors may be the point at which the apparent partner specificity of the disease originates. The second stage is the maternal syndrome, which is characterized by a generalized systemic inflammatory response involving both leukocytes and endothelium. The inflammatory stimulus is believed to come from the placenta. In pre-eclampsia, placental oxidative stress may lead to increased shedding of apoptotic and/or necrotic syncytiotrophoblast debris into the maternal circulation. There is evidence that such trophoblast debris interacts with maternal leukocytes and endothelial cells to stimulate the release of proinflammatory cytokines, which could then trigger the maternal disease.

Female↗

PubMed2005

Differential expression of alternatively spliced transcripts of HLA-G in human preimplantation embryos and inner cell masses.

It has been reported that preimplantation human embryos secrete HLA-G, and the levels may be predictive of their ability to implant. However, it is not known which of the membrane-bound (HLA-G 1-4) and soluble (HLA-G 5-6) alternatively spliced forms are present, nor the developmental stage at which they appear. Therefore, we have investigated HLA-G mRNA isoform expression on single embryos at the two-, four-, six-, and eight-cell, morula, and blastocyst stages. The percentage of embryos expressing each HLA-G isoform mRNA increased with developmental stage, but contrary to expectation, HLA-G5 mRNA was not detected in single two- to eight-cell embryos and was only expressed by 20% of morulae and blastocysts. Similarly, soluble HLA-G6 mRNA was not detected until the blastocyst stage and then in only one-third of embryos. In contrast, labeling with MEM G/9 Ab (specific for HLA-G1 and -G5) was observed in 15 of 20 two- to eight-cell embryos and 5 of 5 blastocysts. This disparity between mRNA and protein may be due to HLA-G protein remaining from maternal oocyte stores produced before embryonic genome activation and brings into question the measurement of soluble HLA-G for clinical evaluation of embryo quality. Although HLA-G is expressed in the preimplantation embryo, later it is primarily expressed in the invasive trophoblast of the placenta rather than the fetus. Therefore, we have investigated whether down-regulation of HLA-G first occurs in the inner cell mass (precursor fetal cells) of the blastocyst and, in support of this concept, have shown the absence HLA-G1 and -G5 protein and mRNA.

Alternative Splicing↗

PubMed2005

Latest advances in understanding preeclampsia.

Preeclampsia is a relatively common pregnancy disorder that originates in the placenta and causes variable maternal and fetal problems. In the worst cases, it may threaten the survival of both mother and baby. We summarize recent work on the causes of preeclampsia, which reveals a new mode of maternal immune recognition of the fetus, relevant to the condition. The circulating factors derived from the placenta, which contributes to the clinical syndrome, are now better understood. This brief review on preeclampsia does not cover all aspects of this intriguing condition but focuses on some new and interesting findings.

Animals↗

PubMed2005

Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells.

A bias of T cell immunity towards type 2 (Th2) is thought to be critical for normal pregnancy. Pathological pregnancies, such as pre-eclampsia, are characterised by cell-mediated (Th1) immune dominance. The Th1/Th2 paradigm, however, is too simplistic. Normal pregnancy is associated with a systemic inflammatory response which increases throughout gestation. This inflammatory response is exaggerated in pre-eclampsia, a syndrome of the third trimester. T helper (Th) cells are considered the primary mediators of these altered immune responses, and other T cells, i.e. T cytotoxic (Tc) cells, and lymphocytes of the innate immune system, i.e. natural killer (NK) and NKT cells, have been largely disregarded. In this study, we have used novel pan type 1 (IL-18 receptor) and pan type 2 (ST2L) lymphocyte function markers in four-colour flow cytometry to broadly characterise peripheral blood lymphocyte populations from non-pregnant, normal pregnant and pre-eclamptic women. There were no changes in the Th1/Th2 or Tc1/Tc2 cell ratios between the three groups; however, the NK1/NK2 and NKT1/NKT2 cell ratios were significantly decreased in normal pregnancy compared with non-pregnant (p <0.001 and p <0.01, respectively) and pre-eclamptic women (p <0.05). These results confirm that immunoregulation occurs in pregnancy, but suggest a dominant role of the innate rather than the adaptive immune system.

Adult↗

PubMed2005

Immunological properties of human decidual macrophages--a possible role in intrauterine immunity.

Our aim was to investigate the contribution of decidual macrophages, which constitute an important immune component of the decidua in late gestation, to intrauterine defence mechanisms. Using flow cytometry we examined the ability of decidual macrophages, isolated from term decidua, to bind and phagocytose fluorescence-labelled bacterial and yeast bioparticles. We also assessed their ability to generate superoxide radicals and tumour necrosis factor-alpha following lipopolysaccharide challenge. Decidual macrophages bound bacterial and yeast particles in a dose-dependent manner, which subsequently led to phagocytosis. These macrophages also produced superoxide radicals and the pro-inflammatory cytokine TNF-alpha when challenged with bacterial lipopolysaccharides. These results suggest a role for decidual macrophages in pathogen recognition and clearance during pregnancy, and, therefore, they are likely to protect the fetus against intrauterine infections which might otherwise lead to preterm labour.

Cell Count↗

PubMed2004

Adrenomedullin: multiple functions in human pregnancy.

Adrenomedullin is a 52 amino acid peptide originally isolated from human phaeochromocytoma in 1993. It was initially demonstrated to have profound effects on the vasculature including vasodilatation and subsequently promotion of angiogenesis. Since then it has become apparent that it has a wide range of other biological actions including regulation of cell growth and differentiation. Successful pregnancy outcome relies on establishing and maintaining throughout gestation an efficient blood supply to the fetus. This allows the exchange of nutrients, oxygenation of fetal blood and removal of cytotoxins from the fetus, such as carbon dioxide. One of the most important local adaptations to pregnancy is the change in maternal blood flow to the implantation site. Evidence now points towards a vital role for adrenomedullin in the regulation of placentation. It appears that adrenomedullin may play important roles in the regulation of fetal perfusion both in normal and in compromised pregnancies. However, most studies have focused on measuring adrenomedullin levels and studying its expression as well as that of its receptors. More functional studies are now required to elucidate the underlying mechanisms involved.

Adrenomedullin↗

PubMed2004

Preeclampsia and the systemic inflammatory response.

Normal pregnancy is associated with a systemic inflammatory response. The response is exacerbated in preeclampsia and can account for its clinical features. Many of the physiologic changes of normal pregnancy are part of an acute-phase reaction, which is generated by an inflammatory response. The placenta is the proximal cause of these problems. There are several possible placental factors that may evoke the inflammatory responses that currently are being investigated. The special susceptibility of obese women, or those with diabetes or chronic hypertension, to preeclampsia is explained by the chronic systemic inflammatory responses that these women have. The clinical implications of these concepts are discussed.

Female↗

PubMed2003

Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia.

OBJECTIVE: Tryptophan degradation and depletion resulting from activation of indoleamine 2,3-dioxygenase is characteristic of inflammatory reactions and may control their intensity. Normal third-trimester pregnancy is characterized by a maternal systemic inflammatory response, which is more intense in preeclampsia. Therefore, we studied tryptophan metabolism in pregnant women, with or without preeclampsia, as well as expression and function of placental indoleamine 2,3-dioxygenase. STUDY DESIGN: Plasma concentrations of tryptophan and kynurenine in women with preeclampsia, appropriately matched women with normal pregnancy, and healthy nonpregnant women were measured. Placental enzymatic activity and messenger RNA (mRNA) expression level of indoleamine 2,3-dioxygenase were determined from the same placental material. Peripheral blood mononuclear cell proliferation was determined in medium conditioned by prior culture with villous tissue. RESULTS: The plasma ratio of kynurenine to tryptophan, an in vivo index of enzyme activity, was significantly increased compared with nonpregnant controls in normal pregnancy but not in preeclampsia. The activity and mRNA expression level of indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Medium conditioned by culture of villous tissue explants of preeclampsia was less effective in inhibiting peripheral blood mononuclear cell proliferation compared with that of normal pregnancy. CONCLUSION: These observations suggest that in preeclampsia, reduced placental indoleamine 2,3-dioxygenase activity (and relatively elevated plasma tryptophan) could cause dysregulation of the inflammatory response that is intrinsic to normal pregnancy. This may contribute to the pathogenesis of the maternal syndrome of preeclampsia.

Adult↗

PubMed2002

Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst.

The mechanisms that mediate implantation of the human embryo remain poorly understood and represent a fundamental problem in reproductive biology. Candidate molecules that mediate and facilitate implantation have been identified in animal studies, and include heparin binding epidermal growth factor. Here we demonstrate a potential function for the transmembrane form of heparin-binding epidermal growth factor in mediating blastocyst attachment to the endometrium, in two different novel in vitro models for human implantation. Furthermore, we demonstrate specific localisation of the heparin-binding epidermal growth factor receptor ErbB4, on the surface of the trophectoderm in peri-implantation human blastocysts. Our data lead the way for further dissection of the molecular mechanisms of implantation of the human embryo, and have implications for infertility, in vitro fertilization and contraception.

Animals↗