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Journal ArticleDOI

A leading role for the immune system in the pathophysiology of preeclampsia

01 Aug 2013-Journal of Leukocyte Biology (J Leukoc Biol)-Vol. 94, Iss: 2, pp 247-257
TL;DR: The pathophysiology of preeclampsia may involve several factors, including persistent hypoxia at the placental level and the release of high amounts of STBMs, which may contribute to the inflammatory process and to changes in adaptive‐immune system cells, which are also modulated in preeclamping.
Abstract: Preeclampsia syndrome is characterized by inadequate placentation, because of deficient trophoblastic invasion of the uterine spiral arteries, leading to placental hypoxia, secretion of proinflammatory cytokines, the release of angiogenic and antiangiogenic factors and miRNAs. Although immune-system alterations are associated with the origin of preeclampsia, other factors, including proinflammatory cytokines, neutrophil activation, and endothelial dysfunction, are also related to the pathophysiology of this syndrome. The pathophysiology of preeclampsia may involve several factors, including persistent hypoxia at the placental level and the release of high amounts of STBMs. DAMP molecules released under hypoxic conditions and STBMs, which bind TLRs, may activate monocytes, DCs, NK cells, and neutrophils, promoting persistent inflammatory conditions in this syndrome. The development of hypertension in preeclamptic women is also associated with endothelial dysfunction, which may be mediated by various mechanisms, including neutrophil activation and NET formation. Furthermore, preeclamptic women have higher levels of nonclassic and intermediate monocytes and lower levels of lymphoid BDCA-2(+) DCs. The cytokines secreted by these cells may contribute to the inflammatory process and to changes in adaptive-immune system cells, which are also modulated in preeclampsia. The changes in T cell subsets that may be seen in preeclampsia include low Treg activity, a shift toward Th1 responses, and the presence of Th17 lymphocytes. B cells can participate in the pathophysiology of preeclampsia by producing autoantibodies against adrenoreceptors and autoantibodies that bind the AT1-R.
Citations
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Journal ArticleDOI
TL;DR: The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angIogenic factors.
Abstract: Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 5-8% It is one of the main causes of maternal and perinatal morbidity and mortality globally and accounts for 50 000-60 00 deaths annually, with a predominance in the low- and middle-income countries It is a multi-systemic disorder however its aetiology, pathogenesis and pathophysiology are poorly understood Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors This review covers the latest thoughts on the pathogenesis and pathology of pre-eclampsia The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors This imbalance in favour of anti-angiogenic factors leads to widespread endothelial dysfunction, affecting all the maternal organ systems In addition, there is foetal growth restriction (FGR) The exact aetiology remains elusive

266 citations


Cites background from "A leading role for the immune syste..."

  • ...In early-onset PE, oxidative stress caused by low oxygen tension or by disruption of the oxygen-sensing mechanism in placentas is believed to cause over-expression of hypoxia inducible factor-1 (HIF-1α) in placental tissue, and also to the release of increased levels into the circulation.(65) In normal pregnancy, placental expression and formation of HIF-1α increased in a hypoxic environment during the first trimester and this was paralleled by TGF-β3, of which early trophoblast differentiation and placental expression of both molecules remained high until about the 10th gestational week when placental O2 levels began to increase....

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  • ...Perhaps in a similar manner, there is over-expression of genes responsible for the formation of sFlt-1, PlGF and VEGF in PE placentas.(65,68) However, it has to be noted that for ethical reasons, it is difficult to study gene expression in placentas prior to actual clinical diagnosis of PE....

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Journal ArticleDOI
TL;DR: The role of sterile inflammation in reproduction, including early implantation and pregnancy complications is discussed, and major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA are focused on while giving an overview of the potential role of other candidate alarmins.
Abstract: Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.

173 citations

Journal ArticleDOI
TL;DR: New insights are provided about roles of oxidative stress in the pathophysiology of PE and placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria.
Abstract: Preeclampsia (PE) is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of nitric oxide (NO) and tissue damage caused by increased levels of reactive oxygen species (ROS). Furthermore, superoxide (O2−) rapidly inactivates NO and forms peroxynitrite (ONOO−). It is known that ONOO− accumulates in the placental tissues and injures the placental function in PE. In addition, ROS could stimulate platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. The disorders could lead to the reduction of oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the other hand, several antioxidants scavenge ROS and protect tissues against oxidative damage. Placental antioxidants including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) protect the vasculature from ROS and maintain the vascular function. However, placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria. Oxidative stress is defined as an imbalance between ROS and antioxidant activity. This review provides new insights about roles of oxidative stress in the pathophysiology of PE.

160 citations


Cites background from "A leading role for the immune syste..."

  • ...Preeclamptic placenta is known to be hypoxic and stimulate the release of a large amount of syncytiotrophoblast microparticle (STBM) [15]....

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Journal ArticleDOI
11 Jan 2018-PLOS ONE
TL;DR: Dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant), with a significant increase in M2macrophage markers, suggesting that M2 is the predominant macrophages phenotype in thedecidua.
Abstract: It is increasingly evident that cytokines and growth factors produced in the decidua play a pivotal role in the regulation of the local immune microenvironment and the establishment of pregnancy. One of the major growth factors produced in the decidua is vascular endothelial growth factor (VEGF), which acts not only on endothelial cells, but also on multiple other cell types, including macrophages. We sought to determine whether decidua-derived VEGF affects macrophage recruitment and polarization using human endometrial/decidual tissue samples, primary human endometrial stromal cells (ESCs), and the human monocyte cell line THP1. In situ hybridization was used for assessment of local VEGF expression and immunohistochemistry was used for identification and localization of CD68-positive endometrial macrophages. Macrophage migration in culture was assessed using a transwell migration assay, and the various M1/M2 phenotypic markers and VEGF expression were assessed using quantitative real-time PCR (qRT-PCR). We found dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant), with a significant increase in M2 macrophage markers, suggesting that M2 is the predominant macrophage phenotype in the decidua. However, decidual samples from preeclamptic pregnancies showed a significant shift in macrophage phenotype markers, with upregulation of M1 and downregulation of M2 markers. In THP1 cultures, VEGF treatment significantly enhanced macrophage migration and induced M1 macrophages to shift to an M2 phenotype. Moreover, treatment with conditioned media from decidualized ESCs induced changes in macrophage migration and polarization similar to that of VEGF treatment. These effects were abrogated by the addition of a potent VEGF inhibitor. Together these results suggest that decidual VEGF plays a significant role in macrophage recruitment and M2 polarization, and that inhibition of VEGF signaling may contribute to the shift in macrophage polarity observed in different pregnancy disorders, including preeclampsia.

139 citations

Journal ArticleDOI
TL;DR: There is no “cure” for PE except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms and a risk factor for long-term health in women.
Abstract: Preeclampsia (PE) is a pregnancy-specific syndrome and one of the leading causes of preterm birth, neonatal and maternal morbidity and mortality. This disease is characterized by new onset hypertension usually in the third trimester of pregnancy and is sometimes associated with proteinuria, although proteinuria is not a requirement for the diagnosis of PE. In developing countries, women have a higher risk of death due to PE than more affluent countries and one of the most frequent causes of death is high blood pressure and stroke. Although PE only affects approximately 2%-8% of pregnancies worldwide it is associated with severe complications such as eclampsia, hemorrhagic stroke, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and pulmonary edema. Importantly, there is no "cure" for the disease except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms. In addition, PE is linked to the development of cardiovascular disease and stroke in women after reproductive age, leaving PE a risk factor for long-term health in women. This review will highlight factors implicated in the pathophysiology of PE that may contribute to long-term effects in women with preeclamptic pregnancies.

137 citations


Cites background from "A leading role for the immune syste..."

  • ...These cells can also be recruited and activated by increased IL-17.(89) These cells may contribute to the increased vascular resistance and fetal morbidity of PE through production of oxidative stress and the release of neutrophil extracellular traps (NETs)....

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  • ...Oxidative stress-induced inflammation and vascular damage and dysfunction may be attributable in part to the activation of neutrophils and subsequent release of NETs in response to hypoxia and IL-17 signaling during PE and requires further study.(89,117)...

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  • ...These cells may contribute to the increased vascular resistance and fetal morbidity of PE through production of oxidative stress and the release of neutrophil extracellular traps (NETs).(89,117) NETs are extracellular structures released from neutrophils that kill extracellular bacteria and fungi, but are implicated in pathogenesis of inflammatory disorders and autoimmunity....

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  • ...NETs are extracellular structures released from neutrophils that kill extracellular bacteria and fungi, but are implicated in pathogenesis of inflammatory disorders and autoimmunity.(89,117) Oxidative stress-induced inflammation and vascular damage and dysfunction may be attributable in part to the activation of neutrophils and subsequent release of NETs in response to hypoxia and IL-17 signaling during PE and requires further study....

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  • ...These cells can also be recruited and activated by increased IL-17....

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References
More filters
Journal ArticleDOI
TL;DR: Dendritic cells are antigen-presenting cells with a unique ability to induce primary immune responses and may be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response.
Abstract: Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

6,758 citations


"A leading role for the immune syste..." refers background in this paper

  • ...sponses [112], the decreased number of lymphoid DCs in...

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Journal ArticleDOI
12 Apr 2002-Science
TL;DR: A model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign is outlined.
Abstract: For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.

4,082 citations


"A leading role for the immune syste..." refers background in this paper

  • ...According to the danger model [48], hypoxia can lead to a persistent inflammatory response, and this may occur in preeclamptic patients....

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Journal ArticleDOI
TL;DR: It is confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt 1 that fall after delivery, and observations suggest that excess circulating sFelt1 contributes to the pathogenesis of preeClampsia.
Abstract: Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

3,613 citations

Journal ArticleDOI
TL;DR: The role of NF-κB proteins as potential therapeutic targets in clinical applications and their role in the immune system and inflammatory diseases are discussed.
Abstract: The nuclear factor-kappaB (NF-kappaB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-kappaB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-kappaB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-kappaB proteins as potential therapeutic targets in clinical applications.

3,603 citations

Journal ArticleDOI
TL;DR: Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeClampsia was associated with a small-for-gestational-age infant.
Abstract: Background The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascul...

3,148 citations


"A leading role for the immune syste..." refers background in this paper

  • ...High levels of sFlt1 and low levels of PlGF may predict the subsequent development of preeclampsia, as it may be detected 5 weeks before its onset [29]....

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