PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of sprsxLink to Publisher's site
 
Reprod Sci. 2013 April; 20(4): 339–353.
PMCID: PMC3823393

Innate Immunity, Decidual Cells, and Preeclampsia

Chang-Ching Yeh, MD,1,2 Kuan-Chong Chao, MD,2,3 and S. Joseph Huang, MD, PhDcorresponding author1

Abstract

Preeclampsia (PE) manifested by hypertension and proteinuria complicates 3% to 8% of pregnancies and is a leading cause of fetal–maternal morbidity and mortality worldwide. It may lead to intrauterine growth restriction, preterm delivery, and long-term sequelae in women and fetuses, and consequently cause socioeconomic burden to the affected families and society as a whole. Balanced immune responses are required for the maintenance of successful pregnancy. Although not a focus of most studies, decidual cells, the major resident cell type at the fetal–maternal interface, have been shown to modulate the local immune balance by interacting with other cell types, such as bone marrow derived-immune cells, endothelial cells, and invading extravillous trophoblasts. Accumulating evidence suggests that an imbalanced innate immunity, facilitated by decidual cells, plays an important role in the pathogenesis of PE. Thus, this review will discuss the role of innate immunity and the potential contribution of decidual cells in the pathogenesis of PE.

Keywords: innate immunity, decidual cell, preeclampsia, immune cell

Introduction

Preeclampsia (PE) is characterized by the development of hypertension and proteinuria after 20 weeks of pregnancy and is a leading cause of fetal–maternal morbidity and mortality.1,2 PE is a systemic inflammatory disease that may lead to multiple maternal organ damage in liver, kidneys, lungs, and central nervous system.3 In addition, the long-term risks of cardiovascular, cerebrovascular, and renal diseases are increased in women with a history of PE.4,5 Fetuses in pregnancies complicated with PE are at risk of placenta abruption, intrauterine growth restriction, and preterm birth.6 Furthermore, an increasing body of evidence indicates that PE-related prematurity predisposes to chronic lung diseases, cardiovascular diseases, and intellectual and behavioral problems in the child’s later life.79 Delivery of the placenta remains the only effective treatment for PE. Most of the symptoms disappear within a week after delivery. Thus, the decision to deliver warrants thoughtful consideration of the balance between maternal well-being and fetal maturity. A number of biological (fetal cells, cell-free fetal DNA, and RNA), biochemical (angiogenic factors, placental protein 13, pregnancy-associated plasma protein A, and pentraxin 3), and biophysical markers (uterine artery Doppler and arterial blood pressure) have been proposed to predict PE.10 However, none of these markers, alone or in combination, demonstrate satisfactory effectiveness for predicting PE.

To date, the pathogenesis of PE remains unknown. The prevailing hypotheses focus on abnormal placentation (shallow trophoblast invasion and impaired vascular remodeling) in early pregnancy11 that leads to the release of specific molecules (eg, soluble fms-like tyrosine kinase 1 [sFlt-1]) into circulation. Ultimately, symptomatic systemic inflammation and endothelial dysfunction develop.3,6 Balanced immune responses are required for tolerating the fetal semi-allograft yet defending against pathogens. Immune maladaptation at the fetal–maternal interface is suggested to play an important role in the pathogenesis of abnormal placentation.12 Innate immunity, the first line of host defense, plays a pivotal role in recognizing and reacting to the invading signals. Aberrant infiltration of antigen-presenting cells ([APCs] ie, macrophages [MΦs] and dendritic cells [DCs]) has been demonstrated in preeclamptic decidua.13 Interestingly, decidual cells, the major resident cells at the fetal–maternal interface, are shown to secrete an array of cytokines and chemokines that are crucial in modulating local immune responses.14 In this review article, we will discuss the roles of various components in innate immunity in the pathogenesis of PE. The interactions between decidual cell and these components in the pathogenesis of PE will also be reviewed.

Immune System and Innate Immunity

The host defense against immune challenges requires coordination between innate and adaptive elements of immunity. As the first line of defense against exogenous challenges, the innate immune system launches an initial, nearly instantaneous, and relatively nonspecific response to potential pathogens at the site of invasion by granulocytes, MΦs, DCs, and natural killer (NK) cells. Phagocytosis, recognition of the pathogen by pattern-recognition receptors, and cytotoxicity play major roles in mediating the functions of these cells.15 The subsequent highly specific, albeit slower, adaptive immune response, composed of humoral and cellular arms, provides a far more efficient and long-term suppression of pathogens via B and T lymphocytes. While an innate immune response does not require a preceding or simultaneous immune response, an adaptive response does require a leading innate response. Both MΦs and DCs are the two primary APCs that play integral roles in synchronizing both elements of the immune system. The APCs, particularly DCs, are also inducers of immune tolerance by secreting anti-inflammatory cytokines, activating regulatory T cells (Treg cells), or inducing T cell anergy.1618 Thus, MΦs and DCs are uniquely capable of modulating the balance between the innate and adaptive immune systems to provide protection against pathogens yet confer immune tolerance.19,20 Impaired cross talk among the different components in the immune system plays an important role in the pathogenic mechanisms and may affect the severity and outcome of diseases associated with immune maladaptation, such as PE.

Pregnancy and Immunity

Successful pregnancy requires coordination between a receptive endometrium and the implanting blastocyst. The human uterus is an immune-modulated site that segregates the implanted semi-allogeneic embryo from an aggressive maternal immune response defending against pathogens. The exact mechanism of maternal tolerance to the fetal semi-allograft remains unclear. The coordination of various mechanisms is required to ensure effective tolerance. Upon fetal antigen presentation by decidual APCs (mainly DCs), Treg cells are postulated to execute fetal protection2123 by either cell-to-cell contact via inhibitory molecules, such as cytotoxic T lymphocyte antigen-424 and programmed cell death 1,25 or secretion of such immunosuppressive cytokines as interleukin (IL)-10, leukemia inhibitory factor (LIF), transforming growth factor β (TGF-β), and heme oxygenase 1.26 Moreover, galectin 1 secreted by Treg cells may facilitate activated T cell apoptosis and promote anti-inflammatory response.2729 In addition, the unique expression of human leukocyte antigen (HLA)-G, a nonclassical major histocompatibility complex (MHC) class I molecule, by extravillous trophoblasts (EVTs) is demonstrated to be immunosuppressive via its interaction with decidual immune cells.30 Furthermore, indoleamine 2,3-dioxygenase (IDO) expressed by EVTs and decidual cells31,32 is known to catabolize tryptophan to produce kynurenine and picolinic acids that inhibits the cytotoxicity of T cells and NK cells.33,34 It is an imbalance of these immune responses that results in insufficient tolerogenesis to the fetus and leads to adverse pregnancy outcomes, such as miscarriage and PE.3537

A well-regulated cytokine network is crucial for normal immune reactions. Cytokines produced by type 1 CD4+ helper T (Th1) cells are primarily proinflammatory and promote protection against infectious pathogens while that of type 2 CD4+ helper T (Th2) cells are mainly anti-inflammatory and responsible for the regulation of humoral responses. During pregnancy, an array of cytokines are also shown to be expressed by both decidual cells and EVTs in addition to the immune cells.14,38 Pro- and anti-inflammatory immune responses are both postulated to be required for gestation.39 For instance, maternal tolerance to the semi-allogeneic fetus is thought to be related to Th2 immune response, affected by IL-4, IL-5, IL-10, and TGF-β.40 However, proinflammatory Th1 immune response, regulated by IL-1, IL-6, IL-12, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ), are crucial for trophoblast invasion, parturition, and defense against infections.41,42 Therefore, the “balance” between the Th1/Th2 immune responses is mandatory for normal pregnancy. Dysregulation of either arm may result in pathological conditions, such as PE (Figure 1).43

Figure 1.
The Th1/Th2 paradigm and immune balance in pregnancy. The proinflammatory Th1 immune response is responsible for extravillous trophoblast invasion, parturition, and host defense. The anti-inflammatory Th2 reaction is crucial for tolerance to the fetus, ...

Decidual Cells

Decidual cells are the main resident cell type at the fetal–maternal interface, composing 40% of all the cells.44 They are derived from endometrial stromal cells in response to progesterone during the “window of implantation” in the secretory phase of the menstrual cycle and exist throughout pregnancy. The decidualization of endometrial stromal cells is mandatory for successful pregnancy.45 Decidual cells are the major cell type encountered by the invading EVTs. Accumulating evidence shows that decidual cells play numerous important roles in modulating implantation of the blastocyst, EVT invasion, maintenance of oxidative stress resistance, tissue hemostasis, immune responses at the fetal–maternal interface, and their own decidualization by autocrine and paracrine effects (Figure 2). For instance, decidual cell-secreted proprotein convertase 6, LIF, and IL-11 are upregulated during decidualization and embryo implantation,46,47 while deficiency results in implantation failure in mice.4850 Decidual cells express stimulatory IL-1β51,52 and inhibitory TGF-β and LIF52,53 to modulate the balance of metalloproteinase (MMP)/tissue inhibitor of metalloproteinase and urokinase plasminogen activator (uPA)/plasminogen activator inhinitor 1 (PAI-1) systems that are involved in the degradation and remodeling of extracellular matrix in decidua during EVT invasion.54,55 In addition, CX3CL1, CCL4, CCL14, CXCL12, and IL-11 secreted by decidual cells also play roles in controlling EVT invasion with unknown mechanisms.5659 Decidual oxygen pressure suddenly increases during placentation and leads to the generation of harmful reactive oxygen species after tissue oxygen consumption.60 Free radical scavengers, such as superoxide dismutase 2, antioxidative enzyme glutathione peroxidase 3, and GADD45α protein expressed by decidual cells may counteract the oxidative stress.45,61 During decidual tissue and vascular remodeling, tissue factor is highly expressed by decidual cells which promotes physiologic hemostasis.62 Moreover, decidual cells contribute to the development of maternal immune tolerance to fetus by expressing Fas ligand (FasL) that induces apoptosis of activated T cells and IDO which suppresses T cell-dependent inflammatory responses to the fetus.32,61 Cytokines produced by decidual cells are also important for the recruitment of immune cells which are mandatory for tissue remodeling and tolerogenesis.14,63

Figure 2.
Decidual cells in normal pregnancy. As the major cell type encountering the invading extravillous trophoblasts, decidual cells play important roles in modulating implantation of the blastocyst, extravillous trophoblast (EVT) invasion, maintenance of oxidative ...

Impaired decidual cell function results in adverse pregnancy outcomes (Figure 3).13,14,6370 For instance, PE is associated with decidual hemorrhage in which excessive thrombin formation by binding of decidual cell-derived tissue factor to circulating factor VIIa leads to an increased anti-angiogenic sFlt-1 production.64 The aberrant immune cell infiltration observed in PE may attribute to dysregulated chemoattractant production by decidual cells.14 The modulation of EVT invasion by decidual cells may indicate its potential role in the pathogenesis of PE. Excessive MMP-1 and MMP-3 production by decidual cells may predispose to preterm delivery in chorioamnionitis.65

Figure 3.
Decidual cells and the pathogenesis of adverse pregnancy outcomes. In the pathologic setting of inflammation and hemorrhage, decidual cells play important roles in mediating the pathogenesis of adverse pregnancy outcomes. PPROM indicates preterm premature ...

Natural Killer Cells

NK cells are the major immune cell type in the decidua in mid-secretory phase of menstruation cycle and early pregnancy (up to 70%-75%).71 The number of NK cells gradually decreases as pregnancy progresses.7274 Decidual NK cells accumulate around uterine spiral arteries with proximity to EVTs,71,75 indicating their potential role in modulating trophoblast invasion and vascular remodeling. The origin of decidual NK cells remains uncertain. Accumulated evidence suggests that these decidual NK cells may be chemoattracted from peripheral blood and/or differentiated in situ.7678 The proximity of decidual NK cell distribution to the spiral arteries suggests their recruitment from the circulation.79 Such chemokines secreted by EVTs as CCL3, CCL4, and CXCL12 are potential chemoattractants for decidual NK cells.8082 Recent work from our laboratory suggested that decidual cell-derived chemokines, CXCL10 and CXCL11, may also be involved in such chemoattraction.83 However, decidual NK cells are also found in both premenstrual endometrium without trophoblasts and endometrium in ectopic pregnancy, suggesting in situ differentiation of decidual NK cells.84 In murine pregnancy, local differentiation of decidual NK cells has been demonstrated.85 Also, presence of CD34+CD56+ hematopoietic stem cell in human adult endometrium has been reported.86 Interestingly, an in vitro study by Keskin et al illustrated the conversion of peripheral blood NK cell into decidual NK cell phenotype after incubation with TGF-β1.87

Decidual NK cells are unique and phenotypically different from peripheral NK cells. The phenotype of decidual NK cells is predominantly CD56brightCD16 expressing low levels of perforin and high levels of CD94/NKG2 receptor and adhesion-mediating l-selectin88 while the major peripheral NK cell population is CD56dimCD16+ expressing high levels of killer cell immunoglobulin-like receptors (KIRs) and CD57.89 Decidual NK cells display increased immunoregulatory cytokine production but decreased cytotoxic ability compared with peripheral NK cells.9092 The dominance of cytotoxicity or cytokine production of NK cells is determined by a balance of signaling from different cell surface receptors in response to different stimuli.93 The NK cell receptors, including KIR, the C-type lectin heterodimer family (CD94/NKG2), the Ly49 homodimers, the NK cytotoxicity receptors, and the immunoglobulin-like transcripts (ILTs), are either stimulatory or inhibitory or both.94,95

Decidual NK cells are known to produce important cytokines and angiogenic factors, including vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2 (Ang-2), TNF-α, IL-8, IL-10, granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-1β, TGF-β1, macrophage colony-stimulating factor (M-CSF), LIF, and IFN-γ, which are essential for a successful pregnancy.9699 Both IL-8 and CXCL10 expressed by NK cells are shown to stimulate trophoblast invasion.100 In murine pregnancy, decidual NK cell-derived IFN-γ was suggested to promote vascular remodeling by modifying gene expression in uterine vasculature.101 Recent studies showed that the production of IL-1β, GM-CSF, IL-6, IL-8, and IFN-γ by decidual NK cells was increased from 8 to 10 weeks to 12 to 14 weeks during gestation.99,102,103 By contrast, the expression of Ang-2 and VEGF-C by decidual NK cells are found to be lower in 12 to 14 weeks compared with that in 8 to 10 weeks.104 These gestational age-dependent changes of cytokine profile reflect the variability of NK cell function during different periods of pregnancy.105 Besides the cytokines and angiogenic factors, decidual NK cells also secrete MMP2, MMP9, and uPA, which are important for the breakdown of extracellular matrix required for trophoblast invasion and vascular remodeling.106108

EVTs express HLA-C, HLA-G, and HLA-E, rather than HLA-A, HLA-B and MHC class II molecules seen in other human cells.109,110 The HLA molecules expressed by EVTs may potentially be recognized by NK cell receptors. HLA-C binds to KIR2DL1, KIR2DL2, and KIR2DL3.111 Both CD94-NKG2A and CD94-NKG2C are HLA-E receptors.112 HLA-G has high affinity to ILT1 and can be a ligand for KIR2DL4.113,114 The proximity of NK cells and EVTs in the decidua115 indicates that the recognition of HLAs on the invasive EVTs by decidual NK cells may regulate NK cell cytotoxicity as well as the production of various cytokines and angiogenic factors essential for successful pregnancy.100 EVTs are likely protected from cytotoxicity by decidual NK cells through the recognition of HLA-G on EVTs by the inhibitory receptors (either ILT2 or KIR2DL4 or both) on decidual NK cells.114,116120 The binding of HLA-G and KIR receptor is thought to produce cytokines and angiogenic factors, including TNF-α, IL-8, IL-1β, and IFN-γ, which facilitate trophoblast invasion and vascular remodeling.100,121123 Moreover, the interaction between HLA-E on EVTs and CD94/NKG2A on decidual NK cells has been postulated to inhibit killing of trophoblasts.124

Although the distribution of immune cells in the decidua has been extensively investigated in recent years, the association of decidual NK cell infiltration and PE remains controversial. The numbers of NK cells have been found to be either increased or decreased in the preeclamptic decidua.125130 The conflicting results may be due to different methods of isolation and the location of sampling. While PE is believed to exhibit a Th1 immune profile, the Th1/Th2 paradigm has been extended to NK cells (NK1/NK2) with polarization of cytokine secretion.131,132 Compared with normal pregnancies, an increased NK1/NK2 ratio in peripheral NK cell populations was found in PE.133 Also, women with PE were shown to have a significantly lower percentage of peripheral CD56bright/NKp46+ cells than women with normal pregnancy.134 Despite our recent observations revealing an increased secretion of NK cell-recruiting chemokine, CXCL10 and CXCL11, by proinflammatory cytokine-stimulated first trimester decidual cells,83 little is known about the interactions between decidual cell and NK cells. Decidual NK cells, with their interaction with EVTs and the sequential alterations in the effector functions, may play a role in the pathogenesis of PE. PE is found to be more prevalent in pregnancies where maternal NK cells express KIR receptors with the inhibitory AA genotype and HLA-C2-expressing EVTs,135 indicating the association of PE and a relatively inhibited NK cell effector function. Also, low HLA-G expression by EVTs has been demonstrated in the placenta from severe PE.136 Furthermore, increased numbers of CD56+ and CD94+ cells with decreased placental IL-12 expression were found in preeclamptic decidua at delivery compared with healthy controls.126 In contrast, serum IL-12 level was significantly elevated in women with PE.126 Further studies are needed to clarify the potential impact of this NK dysregulation on the pathogenesis of PE.

Macrophages

Second to NK cells in the first trimester decidua, CD14- and CD68-expressing MΦs71,137,138 consist of 20% to 25% of decidual leukocytes. Macrophages mediate both innate and adaptive immunity. Through its versatility in presenting antigens to defend against invading pathogens and the induction of immune tolerance, MΦ plays an important role in the maintenance of normal pregnancy.139,140 Throughout human pregnancy, substantial numbers of decidual MΦs are in the vicinity of invading EVTs,12,141 suggesting their role in mediating both normal and abnormal placentations as well as modulating the placental response to infection.142145 The invasion of EVTs into the decidua and inner third of myometrium transforms the uterine spiral arteries and arterioles into low-resistance, high capacitance vessels that provide sufficient exchange of gas, waste, and nutrients required for fetal–placental development.11,146,147 This vascular remodeling process is characterized by the loss of vascular smooth muscle cells and endothelial cells of the uterine spiral arteries and relining the vessel wall with EVTs.55 With their influx to the implantation site in early pregnancy,148 MΦs modulate vascular remodeling and angiogenesis by secreting VEGF, MMPs, TGF-β, fibroblast growth factor (FGF), fibronectin, osteopontin, and collagen.149,150 Macrophages are also proposed to involve in the degradation of extracellular matrix of local tissue, which promotes EVT invasion.62,151 Furthermore, MΦs phagocytose apoptotic cells in the decidua during the invasion and remodeling process.152 Ingestion of these apoptotic cells may elicit Th2 cytokine secretion by MΦs that plays an important role in the initiation of immune tolerance.153 The subsequent remodeling of the decidua is postulated to facilitate further EVT invasion.152,154 However, incomplete removal of apoptotic cells will lead to the release of intracellular contents from apoptotic bodies and the induction of proinflammatory response of APCs by the secretion of proinflammatory cytokines, such as TNF-α, IL-1β, IL-12, and IFN-γ,155,156 which can cause further tissue damage.157,158

Compared with normal pregnancies, shallow trophoblast invasion and impaired spiral artery remodeling were noted in pregnancies complicated by PE.159161 Aberrant infiltration of MΦs was found in the preeclamptic decidua,13 which supports the postulation that PE is related to excess inflammation.6 Macrophages can be recruited to the decidua by decidual cell- and trophoblast-secreted CCL2, CCL7, CCL4, CCL5, and CXCL814,66,162164 which are increased in preeclamptic decidua.13 A recent study demonstrated that under the stimulation of proinflammatory cytokines (IL-1β and TNF-α), first trimester decidual cells produce an array of MΦ-recruiting chemokines through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinase pathways. Among these first trimester decidual cell-secreted chemokines, CCL2 was shown to be the most potent one in recruiting monocytes/MΦs.164 In addition, the increased production of GM-CSF by decidual cells in preeclamptic decidua also contributes to the differentiation of MΦs and their secretion of proinflammatory cytokines.165 In this setting of excessive inflammation, trophoblast invasion has been shown to be limited by TNF-α produced by MΦs, possibly through the induction of trophoblast apoptosis.13,166,167 Also, activated MΦ-produced PAI-1 and inducible nitric oxide synthase exhibit inhibitory effect on trophoblast invasion and spiral artery remodeling.168,169 Our recent study further demonstrated that proinflammatory cytokine-stimulated first trimester decidual cells enhance MΦ-induced EVT apoptosis, which may account for abnormal placentation.170 Moreover, decidual MΦs regulate placental angiogenesis by secreting VEGF171 which binds to fms-like tyrosine kinase-1 (Flt-1).172 Zhou et al demonstrated that the expression of VEGF and Flt-1 was dysregulated in severe PE.173 In addition, the circulating level of sFlt-1, a competitive antagonist of VEGF produced by alternative splicing of Flt-1,174 is elevated in preeclamptic women.175,176 In recent studies, MΦs are suggested to be an additional source of sFlt-1 which is expressed in response to lipopolysaccharides (LPS) treatment.177,178 Thus, an imbalance of VEGF signaling induced by MΦs is thought to influence placental angiogenesis and the pathogenesis of PE.179

Macrophage exhibits its dual role in both promoting normal pregnancy (such as promotion of vascular remodeling and placental angiogenesis) and in contributing to the development of pathological pregnancies (such as inhibition of trophoblast invasion; Figure 4). These observations suggest the importance of “balance” between cytokine production and intercellular reactions at the fetal–maternal interface that determines the success of uneventful pregnancy. Similar to the concept of Th1/Th2 polarization in effector T cell function, MΦs are proposed to be categorized into either classically activated macrophage (M1) or alternatively activated macrophage (M2) subgroups according to their effector phenotypes in response to specific stimuli.144,156,180 M1 MΦs produce TNF-α and IL-12 and promote inflammatory process after activation by LPS or IFN-γ. In response to IL-4 stimulation, M2 MΦs express IL-10 and IL-13 and engage in tissue repair and tolerogenesis.154 Although the M1/M2 classification provides better understanding and explanation for MΦ function, additional evidence is required to confirm their existence in tissue or specific disease such as PE.88 Recently, Schonkeren et al illustrated an increased number of CD14+ cells in preterm PE placentas compared with idiopathic preterm control placentas. Also, the observations demonstrating the lower CD163+/CD14+ cell ratio (M2) and the higher CD209+/CD14+ cell ratio (M1) in preeclamptic placentas compared with control placentas complement the M1/M2 paradigm.178

Figure 4.
The role of macrophage in normal and preeclamptic pregnancies. With its great versatility, macrophages are important in maintenance of a successful pregnancy. However, if dysregulated, macrophages also contribute to the pathogenesis of preeclampsia. Dashed ...

Dendritic Cells

Complementary to MΦs, DCs are the most potent APCs, which mediate innate immune response and subsequent adaptive immune response. Although DCs consist of 1% to 2% of decidual leukocytes,79 they are crucial for the modulation of the decidual tissue remodeling (including decidualization and angiogenesis), immunologic defense against possible pathogens, and the induction of immune tolerance at the fetal–maternal interface (Figure 5).

Figure 5.
The role of dendritic cells in pregnancy. Under the influence of cytokines and recruiting chemokines such as GM-CSF, dendritic cells modulate host defense, decidualization, angiogenesis, and development of immune tolerance during implantation and pregnancy. ...

During implantation, the fetal semi-allograft induces the production of GM-CSF by endometrial epithelial cells181,182 that plays an important role in the development of uterine DCs.183 Through the synthesis of an array of pro-angiogenic (VEGF,184 FGF-2,185 TNF-α,186 IL-6,187 TGF-β,187 CXCL8,185 CCL2,188 and endothelin 1185) and anti-angiogenic (sFlt-1,189 IL-12,190 IL-18,188 thrombospondin 1,191 and pentraxin 3191) molecules, DCs are suggested to foster the decidualization and angiogenesis required for successful implantation and subsequent placentation.189,192,193 In addition, TGF-β expressed by uterine DCs may suppress cytotoxic CD8+ T cell function and promote the development of Treg cells, which play major role in immune tolerance.194 Furthermore, recognition of HLA-G on EVTs by inhibitory receptors ILT2 and ILT4 on decidual DCs195 conveys immunosuppressive signals and modulates anti-inflammatory cytokine production.196 The function of DCs differs based on their maturity. Specifically, immature DCs are postulated to induce T cell anergy, whereas semi-mature DCs promote the development of CD4+CD25+Foxp3+ Treg cells that are responsible for the immune tolerance. Mature DCs exhibit strong antigen-presenting activity that promotes T cell activation and may contribute to the Th1 immune response in preeclamptic decidua.197,198

In normal pregnancy, decidual DCs were demonstrated to be mainly immature DCs.199 Under the influence of cytokines, such as GM-CSF, DCs modulate decidualization, angiogenesis, and development of immune tolerance during implantation and pregnancy. Either excess or deficiency in DC function may lead to adverse pregnancy outcomes. Deficient GM-CSF expression was shown to result in impairment of T cell activation by uterine DCs in mice, which may be related to the immune maladaptation found in miscarriage.200 Ablation of uterine DCs had been demonstrated to result in failure of decidualization, impaired implantation, and increased embryo resorption in mice.201

The number of DCs and the levels of their recruiting chemokines (CCL2, CCL4, CCL7, and CCL20) have been shown to be elevated in preeclamptic decidua compared with gestation age-matched controls.13 However, different from MΦs, DCs did not show effect in impeding trophoblast invasion in vitro.13 Interestingly, an increased expression of GM-CSF, a potent differentiation inducer and activator of DCs, in preeclamptic decidua was demonstrated in both in vivo animal study and in situ human tissue staining.165 In addition, the aberrant first trimester decidual cell-derived GM-CSF induced by proinflammatory stimuli has been shown to enhance the development of DCs.165 Together, these observations suggest that the increased recruitment and activation of DCs by decidual cell-secreted DC-recruiting chemokines and GM-CSF in decidua play a critical role in the pathogenesis of PE (Figure 5).

Toll-Like Receptors

Both MΦs and DCs recognize the pathogenic molecules and “danger signals” via toll-like receptors (TLRs) expressed on the cell surface and in the cytoplasm. In addition to APCs, TLR2 and TLR4 are found to be expressed in first trimester decidual cells,202 Hofbauer cells, villous cytotrophoblasts, and EVTs, but not in syncytiotrophoblasts, indicating the role of placenta as a barrier in protecting the fetus from infectious molecules.145,202204 The binding of TLRs and danger signals will trigger the host immune responses, including immune cell recruitment, cytokine production, and the activation of adaptive immune response.205,206 As members of pattern-recognition receptors, 10 TLRs207 selectively recognizing different pathogen-associated molecular patterns have been identified.208 Specifically, TLR4 recognizes paclitaxel and LPS from gram-negative bacteria;209 while TLR2 binds to bacterial lipoproteins, peptidoglycan from gram-positive bacteria, lipoteichoic acid, and fungal zymosan.210212 Besides the pathogens, TLRs may also be activated by endogenous or noninfectious “danger”-associated molecular patterns such as apoptotic cells, extracellular matrix components including fibronectin, oligosaccharides of hyaluronic acid, and heat shock protein.213216 After ligand recognition, most TLRs trigger intracellular signaling pathway via adapter protein myeloid differentiation factor 88 (MyD88), which in turn activates the NFκB pathway leading to the production of inflammatory cytokines.217 Both TLR3 and TLR4 are able to signal in a MyD88-independent manner through adaptor protein Toll/IL-1 receptor-domain-containing adaptor inducing interferon β (TRIF) pathway not only to activate NFκB cascade but also to result in secretion of interferon.218

The excessive proinflammatory response associated with PE is proposed to be mediated by TLRs via the recognition of danger signals, including infectious pathogens and anti-phospholipid antibodies.219222 An increasing body of evidence shows that infectious agents may predispose the proinflammatory status and abnormal placentation observed in PE, in which the TLR is playing a role.223 For instance, in vivo animal studies revealed that injection of low-dose endotoxin to pregnant rats induced PE-like pathological changes.224 Also, sustained activation of TLR3 was shown to trigger PE-like symptoms in rats.225 Studies involving TLRs and the pathogenesis of PE are focused on trophoblasts. Although TLRs are expressed on decidual cells, their functions and interactions with other local immune cells during the pathogenesis of PE are still unclear. The association of PE and maternal infection has been revealed by epidemiological studies showing elevated antibody titers for Chlamydia pneumonia and cytomegalovirus in patients with PE.226230 In vitro studies showed that with the binding of TLR3 by poly (I:C) or TLR4 by LPS, the cytokine secretion by trophoblast was significantly increased and subsequently lead to monocyte chemotaxis.162,231,232 Poly (I:C) stimulation of TLR3 on trophoblast was also found to provoke the production of anti-angiogenic sFlt-1.233 The expression of TLR4 was demonstrated to be elevated in trophoblasts from patients with PE.234 Recently, the correlation between single-nucleotide polymorphisms (SNPs) of TLR has been described. Both TLR2 and TLR4 SNPs are postulated to alter susceptibility to developing PE.235 Common mutations in TLR4 (D299G and T399I) and NOD2 (R702W, G908R and L1007fs) were demonstrated in patients with history of PE.236 However, the presence of SNPs of the TLR4 gene: Asp299Gly (A896G) and Thr399Ile (C1196T) were not significantly related to PE in a Caucasian population.237 Further studies are required in exploring the effect of SNPs on PE.

Summary

PE, characterized by maternal hypertension and proteinuria after 20 weeks of gestation, remains a major threat to maternal and fetal health during pregnancy. The pathogenesis of PE is believed to be multifactorial involving abnormal placentation, excessive oxidative stress, impaired angiogenesis, and immunological maladaptation. Decidual cells, one of the major cell types at the fetal–maternal interface, yet least studied, have been shown to play potential key roles in modulating cell interaction and function in recent studies. Innate immunity, being the first direct contact with the fetal semi-allograft, plays a crucial role in maintaining successful pregnancy by keeping maternal–fetal immune tolerance and protecting against possible pathogens. Various mediators of the innate immune response, coordinately or independently, exert differential functions in normal pregnancy and PE by interacting with decidual cells (Table 1). Through secretion of cytokines, decidual cells are shown to be involved in the aberrant infiltration of MΦs and DCs in the proinflammatory preeclamptic decidua.13 Functional studies demonstrated that proinflammatory cytokine-stimulated first trimester decidual cells contribute to excess trophoblast apoptosis and the impediment of trophoblast invasion via interaction with MΦs. Also, excessive thrombin formation resulting from binding of decidual cell-secreted tissue factor to factor VIIa cause production of sFlt-1, which is an important anti-angiogenesis factor found in PE. However, researches attempting to demonstrate the interactions between decidual cells, NK cells, and TLRs in the pathogenesis of PE are limited. Further integrated studies are required.

Table 1.
Decidual Immune Cells and Their Roles in Normal Pregnancy and Preeclampsia.

Although PE is the leading complication of pregnancy, the research of PE is hindered by several factors: (1) PE only occurs naturally in humans due to the unique process of human implantation; (2) its symptoms generally appear only late in pregnancy (third trimester), whereas its pathology is usually initiated in early pregnancy (first trimester); (3) despite intense research efforts, there are currently no reliable and conclusive markers identifying those women who will go on to develop PE; (4) ethical proscriptions prevent investigators from using humans as participants to study the pathogenic development of this disorder in the early stage of pregnancy. The majority of the present studies have focused on mechanisms involving a single immune cell type. Investigation of multi-cell interactions including decidual cells or study integrating different pathological mechanisms will provide insight into the establishment of novel diagnostic, therapeutic, and preventative strategies.

Acknowledgments

We are very thankful to Drs Salley Pels and Seth Guller for their critical review and editing of the manuscript.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: National Institute of Child Health and Development, National Institutes of Health R01HD056123 (SJH).

References

1. National Heart L, Blood Institute. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet and Gynecol. 2000;183(1):S1–S22. [PubMed]
2. Duley L. Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol. 1992;99(7):547–553. [PubMed]
3. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631–644. [PubMed]
4. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005;366(9499):1797–1803. [PubMed]
5. Nisell H, Lintu H, Lunell NO, Mollerstrom G, Pettersson E. Blood pressure and renal function seven years after pregnancy complicated by hypertension. Br J Obstet Gynaecol. 1995;102(11):876–881. [PubMed]
6. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–799. [PubMed]
7. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease-the hypothesis revisited. BMJ. 1999;319(7204):245–249. [PMC free article] [PubMed]
8. Levent E, Atik T, Darcan S, Ulger Z, Goksen D, Ozyurek AR. The relation of arterial stiffness with intrauterine growth retardation. Pediatr Int. 2009;51(6):807–811. [PubMed]
9. Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. School-age outcomes in children with birth weights under 750 g. N Engl J Med. 1994;331(12):753–759. [PubMed]
10. Cetin I, Huppertz B, Burton G, et al. Pregenesys pre-eclampsia markers consensus meeting: what do we require from markers, risk assessment and model systems to tailor preventive strategies? Placenta. 2011;32(suppl):S4–S16. [PubMed]
11. Brosens I, Robertson WB, Dixon HG. The physiological response of the vessels of the placental bed to normal pregnancy. J Pathol Bacteriol. 1967;93(2):569–579. [PubMed]
12. Bulmer JN, Sunderland CA. Immunohistological characterization of lymphoid cell populations in the early human placental bed. Immunology. 1984;52(2):349–357. [PubMed]
13. Huang SJ, Chen CP, Schatz F, Rahman M, Abrahams VM, Lockwood CJ. Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua. J Pathol. 2008;214(3):328–336. [PubMed]
14. Huang SJ, Schatz F, Masch R, et al. Regulation of chemokine production in response to pro-inflammatory cytokines in first trimester decidual cells. J Reprod Immunol. 2006;72(1-2):60–73. [PubMed]
15. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol. 2001;13(1):114–119. [PubMed]
16. Groux H, Fournier N, Cottrez F. Role of dendritic cells in the generation of regulatory T cells. Semin Immunol. 2004;16(2):99–106. [PubMed]
17. Mor G, Abrahams VM. Potential role of macrophages as immunoregulators of pregnancy. Reprod Biol Endocrinol. 2003;1:119. [PMC free article] [PubMed]
18. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. [PubMed]
19. Piccinni MP, Romagnani S. Regulation of fetal allograft survival by a hormone-controlled Th1- and Th2-type cytokines. Immunol Res. 1996;15(2):141–150. [PubMed]
20. Rescigno M, Granucci F, Ricciardi-Castagnoli P. Dendritic cells at the end of the millennium. Immunol Cell Biol. 1999;77(5):404–410. [PubMed]
21. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004;5(3):266–271. [PubMed]
22. Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod. 2004;10(5):347–353. [PubMed]
23. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523–532. [PMC free article] [PubMed]
24. Read S, Greenwald R, Izcue A, et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 2006;177(7):4376–4383. [PubMed]
25. Wafula PO, Teles A, Schumacher A, et al. PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod Immunol. 2009;62(5):283–292. [PubMed]
26. Zenclussen AC, Gerlof K, Zenclussen ML, et al. Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface. Eur J Immunol. 2006;36(1):82–94. [PubMed]
27. Garin MI, Chu CC, Golshayan D, Cernuda-Morollon E, Wait R, Lechler RI. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood. 2007;109(5):2058–2065. [PubMed]
28. Dias-Baruffi M, Zhu H, Cho M, Karmakar S, McEver RP, Cummings RD. Dimeric galectin-1 induces surface exposure of phosphatidylserine and phagocytic recognition of leukocytes without inducing apoptosis. J Biol Chem. 2003;278(42):41282–41293. [PubMed]
29. Toscano MA, Commodaro AG, Ilarregui JM, et al. Galectin-1 suppresses autoimmune retinal disease by promoting concomitant Th2- and T regulatory-mediated anti-inflammatory responses. J Immunol. 2006;176(10):6323–6332. [PubMed]
30. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J. 2005;19(7):681–693. [PubMed]
31. Kamimura S, Eguchi K, Yonezawa M, Sekiba K. Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta. Acta Med Okayama. 1991;45(3):135–139. [PubMed]
32. Kudo Y, Hara T, Katsuki T, et al. Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium. Hum Reprod. 2004;19(5):1222–1230. [PubMed]
33. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196(4):459–468. [PMC free article] [PubMed]
34. Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196(4):447–457. [PMC free article] [PubMed]
35. Orsi NM, Tribe RM. Cytokine networks and the regulation of uterine function in pregnancy and parturition. J Neuroendocrinol. 2008;20(4):462–469. [PubMed]
36. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11(5):317–326. [PubMed]
37. Robertson SA, Redman CW, McCracken SA, et al. Immune modulators of implantation and placental development--a workshop report. Placenta. 2003;24 (suppl) A:S16–S20. [PubMed]
38. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol. 1997;37(3):240–249. [PubMed]
39. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010;63(6):425–433. [PMC free article] [PubMed]
40. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993;14(7):353–356. [PubMed]
41. Otun HA, Lash GE, Innes BA, et al. Effect of tumour necrosis factor-alpha in combination with interferon-gamma on first trimester extravillous trophoblast invasion. J Reprod Immunol. 2011;88(1):1–11. [PubMed]
42. Osman I, Young A, Ledingham MA, et al. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Mol Hum Reprod. 2003;9(1):41–45. [PubMed]
43. Saito S, Sakai M. Th1/Th2 balance in preeclampsia. J Reprod Immunol. 2003;59(2):161–173. [PubMed]
44. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inflammation in reproductive disorders. Reprod Sci. 2009;16(2):216–229. [PMC free article] [PubMed]
45. Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445–453. [PubMed]
46. Nie GY, Li Y, Minoura H, Findlay JK, Salamonsen LA. Specific and transient up-regulation of proprotein convertase 6 at the site of embryo implantation and identification of a unique transcript in mouse uterus during early pregnancy. Biol Reprod. 2003;68(2):439–447. [PubMed]
47. Stewart CL, Kaspar P, Brunet LJ, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. [PubMed]
48. Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F, Begley CG. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med. 1998;4(3):303–308. [PubMed]
49. Nie G, Li Y, Wang M, Liu YX, Findlay JK, Salamonsen LA. Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility. Biol Reprod. 2005;72(4):1029–1036. [PubMed]
50. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A. 1991;88(24):11408–11412. [PubMed]
51. Huang HY, Wen Y, Irwin JC, Kruessel JS, Soong YK, Polan ML. Cytokine-mediated regulation of 92-kilodalton type IV collagenase, tissue inhibitor or metalloproteinase-1 (TIMP-1), and TIMP-3 messenger ribonucleic acid expression in human endometrial stromal cells. J Clin Endocrinol Metab. 1998;83(5):1721–1729. [PubMed]
52. Karmakar S, Das C. Regulation of trophoblast invasion by IL-1beta and TGF-beta1. Am J Reprod Immunol. 2002;48(4):210–219. [PubMed]
53. Tapia A, Salamonsen LA, Manuelpillai U, Dimitriadis E. Leukemia inhibitory factor promotes human first trimester extravillous trophoblast adhesion to extracellular matrix and secretion of tissue inhibitor of metalloproteinases-1 and -2. Hum Reprod. 2008;23(8):1724–1732. [PubMed]
54. Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness. Placenta. 2006;27(8):783–793. [PubMed]
55. Burrows TD, King A, Loke YW. Trophoblast migration during human placental implantation. Hum Reprod Update. 1996;2(4):307–321. [PubMed]
56. Dimitriadis E, Nie G, Hannan NJ, Paiva P, Salamonsen LA. Local regulation of implantation at the human fetal-maternal interface. Int J Dev Biol. 2010;54(2-3):313–322. [PubMed]
57. Knofler M, Pollheimer J. IFPA Award in Placentology Lecture: Molecular Regulation of Human Trophoblast Invasion. Placenta. 2012;33(suppl):S55–S62. [PMC free article] [PubMed]
58. Red-Horse K, Drake PM, Gunn MD, Fisher SJ. Chemokine ligand and receptor expression in the pregnant uterus: reciprocal patterns in complementary cell subsets suggest functional roles. Am J Pathol. 2001;159(6):2199–2213. [PubMed]
59. Paiva P, Salamonsen LA, Manuelpillai U, Dimitriadis E. Interleukin 11 inhibits human trophoblast invasion indicating a likely role in the decidual restraint of trophoblast invasion during placentation. Biol Reprod. 2009;80(2):302–310. [PMC free article] [PubMed]
60. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000;157(6):2111–2122. [PubMed]
61. Kajihara T, Jones M, Fusi L, et al. Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. Mol Endocrinol. 2006;20(10):2444–2455. [PubMed]
62. Lockwood CJ, Huang SJ, Krikun G, et al. Decidual hemostasis, inflammation, and angiogenesis in pre-eclampsia. Semin Thromb Hemost. 2011;37(2):158–164. [PMC free article] [PubMed]
63. Lockwood CJ, Paidas M, Krikun G, et al. Inflammatory cytokine and thrombin regulation of interleukin-8 and intercellular adhesion molecule-1 expression in first trimester human decidua. J Clin Endocrinol Metab. 2005;90(8):4710–4715. [PubMed]
64. Lockwood CJ, Toti P, Arcuri F, et al. Thrombin regulates soluble fms-like tyrosine kinase-1 (sFlt-1) expression in first trimester decidua: implications for preeclampsia. Am J Pathol. 2007;170(4):1398–1405. [PubMed]
65. Oner C, Schatz F, Kizilay G, et al. Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery. J Clin Endocrinol Metab. 2008;93(1):252–259. [PubMed]
66. Lockwood CJ, Matta P, Krikun G, et al. Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia. Am J Pathol. 2006;168(2):445–452. [PubMed]
67. Cakmak H, Schatz F, Huang ST, et al. Progestin suppresses thrombin- and interleukin-1beta-induced interleukin-11 production in term decidual cells: implications for preterm delivery. J Clin Endocrinol Metab. 2005;90(9):5279–5286. [PubMed]
68. Lockwood CJ, Arcuri F, Toti P, et al. Tumor necrosis factor-alpha and interleukin-1beta regulate interleukin-8 expression in third trimester decidual cells: implications for the genesis of chorioamnionitis. Am J Pathol. 2006;169(4):1294–1302. [PubMed]
69. Lockwood CJ, Krikun G, Rahman M, Caze R, Buchwalder L, Schatz F. The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. Semin Thromb Hemost. 2007;33(1):111–117. [PubMed]
70. Lockwood CJ, Oner C, Uz YH, et al. Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis factor alpha and interleukin 1 beta in human first trimester decidual cells. Biol Reprod. 2008;78(6):1064–1072. [PMC free article] [PubMed]
71. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod. 1991;6(6):791–798. [PubMed]
72. Hamperl H, Hellweg G. Granular endometrial stroma cells. Obstet Gynecol. 1958;11(4):379–387. [PubMed]
73. Dallenbach-Hellweg G, Nette G. Morphological and Histochemical Observations on Trophoblast and Decidua of the Basal Plate of the Human Placenta at Term. Am J Anat. 1964;115:309–326. [PubMed]
74. Bulmer JN, Lash GE. Human uterine natural killer cells: a reappraisal. Mol Immunol. 2005;42(4):511–521. [PubMed]
75. Loke YW, King A, Burrows TD. Decidua in human implantation. Hum Reprod. 1995;(suppl 2):14–21. [PubMed]
76. Manaster I, Mandelboim O. The unique properties of human NK cells in the uterine mucosa. Placenta. 2008;29 (suppl A): S60–S66. [PubMed]
77. Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int J Dev Biol. 2010;54(2-3):281–294. [PubMed]
78. Wu X, Jin LP, Yuan MM, Zhu Y, Wang MY, Li DJ. Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol. 2005;175(1):61–68. [PubMed]
79. Trundley A, Moffett A. Human uterine leukocytes and pregnancy. Tissue Antigens. 2004;63(1):1–12. [PubMed]
80. Hwang JH, Lee MJ, Seok OS, et al. Cytokine expression in placenta-derived mesenchymal stem cells in patients with pre-eclampsia and normal pregnancies. Cytokine. 2010;49(1):95–101. [PubMed]
81. Kitaya K, Nakayama T, Okubo T, Kuroboshi H, Fushiki S, Honjo H. Expression of macrophage inflammatory protein-1beta in human endometrium: its role in endometrial recruitment of natural killer cells. J Clin Endocrinol Metab. 2003;88(4):1809–1814. [PubMed]
82. Hanna J, Wald O, Goldman-Wohl D, et al. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells. Blood. 2003;102(5):1569–1577. [PubMed]
83. Lockwood CJ, Huang Y, Buchwalder LF, Huang SJ, Schatz F. Interferon-gamma receptors 1 and 2 mediate interferon-gamma-enhanced chemokine expression in human decidual cells. Reprod Sci. 2011;18(3 suppl):151A.
84. von Rango U, Classen-Linke I, Kertschanska S, Kemp B, Beier HM. Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites. Fertil Steril. 2001;76(1):116–124. [PubMed]
85. Bilinski MJ, Thorne JG, Oh MJ, et al. Uterine NK cells in murine pregnancy. Reprod Biomed Online. 2008;16(2):218–226. [PubMed]
86. Lynch L, Golden-Mason L, Eogan M, O'Herlihy C, O'Farrelly C. Cells with haematopoietic stem cell phenotype in adult human endometrium: relevance to infertility? Hum Reprod. 2007;22(4):919–926. [PubMed]
87. Keskin DB, Allan DS, Rybalov B, et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A. 2007;104(9):3378–3383. [PubMed]
88. Bryceson YT, Chiang SC, Darmanin S, et al. Molecular mechanisms of natural killer cell activation. J Innate Immun. 2011;3(3):216–226. [PubMed]
89. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. 2002;2(9):656–663. [PubMed]
90. Higuma-Myojo S, Sasaki Y, Miyazaki S, et al. Cytokine profile of natural killer cells in early human pregnancy. Am J Reprod Immunol. 2005;54(1):21–29. [PubMed]
 91. Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97(10):3146–3151. [PubMed]
 92. Kopcow HD, Allan DS, Chen X, et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci U S A. 2005;102(43):15563–15568. [PubMed]
 93. Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 2004;23(2):255–259. [PubMed]
 94. Lanier LL. NK cell receptors. Annu Rev Immunol. 1998;16:359–393. [PubMed]
 95. Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol. 2001;19:291–330. [PubMed]
 96. Jokhi PP, King A, Sharkey AM, Smith SK, Loke YW. Screening for cytokine messenger ribonucleic acids in purified human decidual lymphocyte populations by the reverse-transcriptase polymerase chain reaction. J Immunol. 1994;153(10):4427–4435. [PubMed]
 97. Rieger L, Kammerer U, Hofmann J, Sutterlin M, Dietl J. Choriocarcinoma cells modulate the cytokine production of decidual large granular lymphocytes in coculture. Am J Reprod Immunol. 2001;46(2):137–143. [PubMed]
 98. Li XF, Charnock-Jones DS, Zhang E, et al. Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells. J Clin Endocrinol Metab. 2001;86(4):1823–1834. [PubMed]
 99. De Oliveira LG, Lash GE, Murray-Dunning C, et al. Role of interleukin 8 in uterine natural killer cell regulation of extravillous trophoblast cell invasion. Placenta. 2010;31(7):595–601. [PubMed]
100. Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12(9):1065–1074. [PubMed]
101. Croy BA, Esadeg S, Chantakru S, et al. Update on pathways regulating the activation of uterine Natural Killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus. J Reprod Immunol. 2003;59(2):175–191. [PubMed]
102. Lash GE, Robson SC, Bulmer JN. Review: functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. Placenta. 2010;31(suppl): S87–S92. [PubMed]
103. Lash GE, Otun HA, Innes BA, et al. Interferon-gamma inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels. FASEB J. 2006;20(14):2512–2518. [PubMed]
104. Lash GE, Schiessl B, Kirkley M, et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol. 2006;80(3):572–580. [PubMed]
105. Lash GE, Bulmer JN. Do uterine natural killer (uNK) cells contribute to female reproductive disorders? J Reprod Immunol. 2011;88(2):156–164. [PubMed]
106. Naruse K, Lash GE, Bulmer JN, et al. The urokinase plasminogen activator (uPA) system in uterine natural killer cells in the placental bed during early pregnancy. Placenta. 2009;30(5):398–404. [PubMed]
107. Naruse K, Lash GE, Innes BA, et al. Localization of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors for MMPs (TIMPs) in uterine natural killer cells in early human pregnancy. Hum Reprod. 2009;24(3):553–561. [PubMed]
108. Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol. 2009;174(5):1959–1971. [PubMed]
109. Le Bouteiller P, Sargent IL. HLA class I molecules in the placenta: which ones, where and what for? A workshop report. Placenta. 2000;21(suppl A):S93–S96. [PubMed]
110. Hviid TV. HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update. 2006;12(3):209–232. [PubMed]
111. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5(3):201–214. [PubMed]
112. Lopez-Botet M, Angulo A, Guma M. Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection. Tissue Antigens. 2004;63(3):195–203. [PubMed]
113. Brown D, Trowsdale J, Allen R. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens. 2004;64(3):215–225. [PubMed]
114. Rajagopalan S, Long EO. A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med. Apr 5 1999;189(7):1093–1100. [PMC free article] [PubMed]
115. Haller H, Radillo O, Rukavina D, et al. An immunohistochemical study of leucocytes in human endometrium, first and third trimester basal decidua. J Reprod Immunol. 1993;23(1):41–49. [PubMed]
116. Chumbley G, King A, Robertson K, Holmes N, Loke YW. Resistance of HLA-G and HLA-A2 transfectants to lysis by decidual NK cells. Cellular Immunol. 1994;155(2):312–322. [PubMed]
117. Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED. The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors? Proc Natl Acad Sci U S A. 1997;94(10):5249–5254. [PubMed]
118. Chen LJ, Han ZQ, Zhou H, Zou L, Zou P. Inhibition of HLA-G expression via RNAi abolishes resistance of extravillous trophoblast cell line TEV-1 to NK lysis. Placenta. 2010;31(6):519–527. [PubMed]
119. Cantoni C, Verdiani S., Falco M, et al. p49, a putative HLA class I-specific inhibitory NK receptor belonging to the immunoglobulin superfamily. Eur J Immunol. 1998;28(6):1980–1990. [PubMed]
120. Colonna M, Navarro F, Bellon T, et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med. Dec 1 1997;186(11):1809–1818. [PMC free article] [PubMed]
121. Sargent IL, Borzychowski AM, Redman CW. NK cells and pre-eclampsia. J Reprod Immunol. 2007;76(1-2):40–44. [PubMed]
122. Rajagopalan S, Bryceson YT, Kuppusamy SP, et al. Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol. 2006;4(1):e9. [PubMed]
123. van der Meer A, Lukassen HG, van Cranenbroek B, et al. Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells. Mol Hum Reprod. 2007;13(2):123–133. [PubMed]
124. Ishitani A, Sageshima N, Hatake K. The involvement of HLA-E and -F in pregnancy. J Reprod Immunol. 2006;69(2):101–113. [PubMed]
125. Stallmach T, Hebisch G, Orban P, Lu X. Aberrant positioning of trophoblast and lymphocytes in the feto-maternal interface with pre-eclampsia. Virchows Archiv. 1999;434(3):207–211. [PubMed]
126. Bachmayer N, Rafik Hamad R, Liszka L, Bremme K, Sverremark-Ekstrom E. Aberrant uterine natural killer (NK)-cell expression and altered placental and serum levels of the NK-cell promoting cytokine interleukin-12 in pre-eclampsia. Am J Reprod Immunol. 2006;56(5-6):292–301. [PubMed]
127. Wilczynski JR, Tchorzewski H, Banasik M, et al. Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2003;109(1):8–15. [PubMed]
128. Williams PJ, Bulmer JN, Searle RF, Innes BA, Robson SC. Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy. Reproduction. 2009;138(1):177–184. [PubMed]
129. Eide IP, Rolfseng T, Isaksen CV, et al. Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis. Virchows Archiv. 2006;448(3):269–276. [PubMed]
130. Rieger L, Segerer S, Bernar T, et al. Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia—a prospective observational study. Reprod Biol Endocrinol. 2009;7:132. [PMC free article] [PubMed]
131. Carter LL, Dutton RW. Relative perforin- and Fas-mediated lysis in T1 and T2 CD8 effector populations. J Immunol. 1995;155(3):1028–1031. [PubMed]
132. Peritt D, Robertson S, Gri G, Showe L, Aste-Amezaga M, Trinchieri G. Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol. 1998;161(11):5821–5824. [PubMed]
133. Borzychowski AM, Croy BA, Chan WL, Redman CW, Sargent IL. Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells. Eur J Immunol. 2005;35(10):3054–3063. [PubMed]
134. Fukui A, Funamizu A, Yokota M, et al. Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy loss, implantation failure and preeclampsia. J Reprod Immunol. 2011;90(1):105–110. [PubMed]
135. Hiby SE, Walker JJ, O'Shaughnessy K M, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200(8):957–965. [PMC free article] [PubMed]
136. Goldman-Wohl DS, Ariel I, Greenfield C, et al. Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Mol Hum Reprod. 2000;6(1):88–95. [PubMed]
137. Rieger L, Honig A, Sutterlin M, et al. Antigen-presenting cells in human endometrium during the menstrual cycle compared to early pregnancy. J Soc Gynecol Investig. 2004;11(7):488–493. [PubMed]
138. Kim JS, Romero R, Cushenberry E, et al. Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor. Placenta. 2007;28(5-6):571–576. [PubMed]
139. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76(3):509–513. [PMC free article] [PubMed]
140. Classen A, Lloberas J, Celada A. Macrophage activation: classical versus alternative. Methods Mol Biol. 2009;531:29–43. [PubMed]
141. Bulmer JN, Smith J, Morrison L, Wells M. Maternal and fetal cellular relationships in the human placental basal plate. Placenta. 1988;9(3):237–246. [PubMed]
142. Smarason AK, Gunnarsson A, Alfredsson JH, Valdimarsson H. Monocytosis and monocytic infiltration of decidua in early pregnancy. J Clin Lab Immunol. 1986;21(1):1–5. [PubMed]
143. Hunt JS, Robertson SA. Uterine macrophages and environmental programming for pregnancy success. J Reprod Immunol. 1996;32(1):1–25. [PubMed]
144. Hunt JS. Current topic: the role of macrophages in the uterine response to pregnancy. Placenta. 1990;11(6):467–475. [PubMed]
145. Abrahams VM, Bole-Aldo P, Kim YM, et al. Divergent trophoblast responses to bacterial products mediated by TLRs. J Immunol. 2004;173(7):4286–4296. [PubMed]
146. Pijnenborg R, Bland JM, Robertson WB, Brosens I. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta. 1983;4(4):397–413. [PubMed]
147. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod. 2003;69(1):1–7. [PubMed]
148. Kabawat SE, Mostoufi-Zadeh M, Driscoll SG, Bhan AK. Implantation site in normal pregnancy. A study with monoclonal antibodies. Am J Pathol. 1985;118(1):76–84. [PubMed]
149. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994;55(3):410–422. [PubMed]
150. Kodelja V, Muller C, Tenorio S, Schebesch C, Orfanos CE, Goerdt S. Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology. 1997;197(5):478–493. [PubMed]
151. Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular-leukocyte interactions: mechanisms of human decidual spiral artery remodeling in vitro. Am J Pathol. 2010;177(2):1017–1030. [PubMed]
152. Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol. 2004;51(4):275–282. [PubMed]
153. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest. 2002;109(1):41–50. [PMC free article] [PubMed]
154. Lala PK, Graham CH. Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev. 1990;9(4):369–379. [PubMed]
155. Yui J, Garcia-Lloret M, Wegmann TG, Guilbert LJ. Cytotoxicity of tumour necrosis factor-alpha and gamma-interferon against primary human placental trophoblasts. Placenta. 1994;15(8):819–835. [PubMed]
156. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35. [PubMed]
157. Hunt JS. Cytokine networks in the uteroplacental unit: macrophages as pivotal regulatory cells. J Reprod Immunol. 1989;16(1):1–17. [PubMed]
158. Straszewski-Chavez SL, Abrahams VM, Mor G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev. 2005;26(7):877–897. [PubMed]
159. Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A. Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 1992;79(1):19–26. [PubMed]
160. Katabuchi H, Yih S, Ohba T, et al. Characterization of macrophages in the decidual atherotic spiral artery with special reference to the cytology of foam cells. Med Electron Microsc. 2003;36(4):253–262. [PubMed]
161. Reister F, Frank HG, Heyl W, et al. The distribution of macrophages in spiral arteries of the placental bed in pre-eclampsia differs from that in healthy patients. Placenta. 1999;20(2-3):229–233. [PubMed]
162. Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005;175(12):8096–8104. [PubMed]
163. Wood GW, Hausmann E, Choudhuri R. Relative role of CSF-1, MCP-1/JE, and RANTES in macrophage recruitment during successful pregnancy. Mol Reprod Dev. 1997;46(1):62–69; discussion 69-70. [PubMed]
164. Li M, Wu ZM, Yang H, Huang SJ. NF{kappa}B and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli. J Clin Endocrinol Metab. 2011;96(8):2502–2511. [PubMed]
165. Huang SJ, Zenclussen AC, Chen CP, et al. The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia. Am J Pathol. 2010;177(5):2472–2482. [PubMed]
166. Reister F, Frank HG, Kingdom JC, et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Invest. 2001;81(8):1143–1152. [PubMed]
167. Renaud SJ, Macdonald-Goodfellow SK, Graham CH. Coordinated regulation of human trophoblast invasiveness by macrophages and interleukin 10. Biol Reprod. 2007;76(3):448–454. [PubMed]
168. Bauer S, Pollheimer J, Hartmann J, Husslein P, Aplin JD, Knofler M. Tumor necrosis factor-alpha inhibits trophoblast migration through elevation of plasminogen activator inhibitor-1 in first-trimester villous explant cultures. J Clin Endocrinol Metab. 2004;89(2):812–822. [PubMed]
169. Pathak N, Sawhney H, Vasishta K, Majumdar S. Estimation of oxidative products of nitric oxide (nitrates, nitrites) in preeclampsia. Aust N Z J Obstet Gynaecol. 1999;39(4):484–487. [PubMed]
170. Wu ZM, Yang H, Li M, et al. Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts. Placenta. 2012;33(3):188–194. [PMC free article] [PubMed]
171. Clark DE, Smith SK, Licence D, Evans AL, Charnock-Jones DS. Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol. 1998;159(3):459–467. [PubMed]
172. Vuorela P, Hatva E, Lymboussaki A, et al. Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biol Reprod. 1997;56(2):489–494. [PubMed]
173. Zhou Y, McMaster M, Woo K, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002;160(4):1405–1423. [PubMed]
174. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993;90(22):10705–10709. [PubMed]
175. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–683. [PubMed]
176. Koga K, Osuga Y, Yoshino O, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab. 2003;88(5):2348–2351. [PubMed]
177. Lee MC, Wei SC, Tsai-Wu JJ, Wu CH, Tsao PN. Novel PKC signaling is required for LPS-induced soluble Flt-1 expression in macrophages. J Leukoc Biol. 2008;84(3):835–841. [PubMed]
178. Schonkeren D, van der Hoorn ML, Khedoe P, et al. Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies. Am J Pathol. 2011;178(2):709–717. [PubMed]
179. Nagamatsu T, Schust DJ. The contribution of macrophages to normal and pathological pregnancies. Am J Reprod Immunol. 2010;63(6):460–471. [PubMed]
180. Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23(4):344–346. [PubMed]
181. Pollard JW, Bartocci A, Arceci R, Orlofsky A, Ladner MB, Stanley ER. Apparent role of the macrophage growth factor, CSF-1, in placental development. Nature. 1987;330(6147):484–486. [PubMed]
182. Robertson SA, Mayrhofer G, Seamark RF. Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice. Biol Reprod. 1992;46(6):1069–1079. [PubMed]
183. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Current Opin Immunol. 2006;18(1):39–48. [PubMed]
184. Conejo-Garcia JR, Benencia F, Courreges MC, et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med. 2004;10(9):950–958. [PubMed]
185. Riboldi E, Musso T, Moroni E, et al. Cutting edge: proangiogenic properties of alternatively activated dendritic cells. J Immunol. 2005;175(5):2788–2792. [PubMed]
186. Curiel TJ, Cheng P, Mottram P, et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 2004;64(16):5535–5538. [PubMed]
187. Verhasselt V, Buelens C, Willems F, De Groote D, Haeffner-Cavaillon N, Goldman M. Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: evidence for a soluble CD14-dependent pathway. J Immunol. 1997;158(6):2919–2925. [PubMed]
188. Piqueras B, Connolly J, Freitas H, Palucka AK, Banchereau J. Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors. Blood. 2006;107(7):2613–2618. [PubMed]
189. Pollard JW. Uterine DCs are essential for pregnancy. J Clin Invest. 2008;118(12):3832–3835. [PubMed]
190. Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 2003;19(5):641–644. [PubMed]
191. Rusnati M, Presta M. Extracellular angiogenic growth factor interactions: an angiogenesis interactome survey. Endothelium. 2006;13(2):93–111. [PubMed]
192. Barrientos G, Tirado-Gonzalez I, Klapp BF, et al. The impact of dendritic cells on angiogenic responses at the fetal-maternal interface. J Reprod Immunol. 2009;83(1-2):85–94. [PubMed]
193. Fainaru O, Adini A, Benny O, et al. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis. Faseb J. 2008;22(2):522–529. [PubMed]
194. Travis MA, Reizis B, Melton AC, et al. Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature. 2007;449(7160):361–365. [PMC free article] [PubMed]
195. Hunt JS, Langat DL. HLA-G: a human pregnancy-related immunomodulator. Curr Opin Pharmacol. 2009;9(4):462–469. [PMC free article] [PubMed]
196. Apps R, Gardner L, Sharkey AM, Holmes N, Moffett A. A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur J Immunol. 2007;37(7):1924–1937. [PMC free article] [PubMed]
197. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 2002;23(9):445–449. [PubMed]
198. Li M, Huang SJ. Innate immunity, coagulation and placenta-related adverse pregnancy outcomes. Thromb Res. 2009;124(6):656–662. [PMC free article] [PubMed]
199. Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod. 2003;69(4):1438–1446. [PubMed]
200. Moldenhauer LM, Keenihan SN, Hayball JD, Robertson SA. GM-CSF is an essential regulator of T cell activation competence in uterine dendritic cells during early pregnancy in mice. J Immunol. 2010;185(11):7085–7096. [PubMed]
201. Plaks V, Birnberg T, Berkutzki T, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest. 2008;118(12):3954–3965. [PubMed]
202. Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S. Expression of Toll-like receptors in the human decidua. Histol Histopathol. 2007;22(8):847–854. [PubMed]
203. Beijar EC, Mallard C, Powell TL. Expression and subcellular localization of TLR-4 in term and first trimester human placenta. Placenta. 2006;27(2-3):322–326. [PubMed]
204. Kumazaki K, Nakayama M, Yanagihara I, Suehara N, Wada Y. Immunohistochemical distribution of Toll-like receptor 4 in term and preterm human placentas from normal and complicated pregnancy including chorioamnionitis. Human Pathol. 2004;35(1):47–54. [PubMed]
205. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–680. [PubMed]
206. Janeway CA, Jr, Medzhitov R. Lipoproteins take their toll on the host. Curr Biol. 1999;9(23):R879–882. [PubMed]
207. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801. [PubMed]
208. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406(6797):782–787. [PubMed]
209. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282(5396):2085–2088. [PubMed]
210. Aliprantis AO, Yang RB, Mark MR, et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science. 1999;285(5428):736–739. [PubMed]
211. Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A. The apoptotic signaling pathway activated by Toll-like receptor-2. Embo J. 2000;19(13):3325–3336. [PubMed]
212. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999;274(25):17406–17409. [PubMed]
213. Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells. Nat Med. 1999;5(11):1249–1255. [PubMed]
214. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem. 2000;275(4):2251–2254. [PubMed]
215. Vabulas RM, Ahmad-Nejad P, da Costa C, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001;276(33):31332–31339. [PubMed]
216. Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol. 2001;167(5):2887–2894. [PubMed]
217. Akira S. Toll-like receptor signaling. J Biol Chem. 2003;278(40):38105–38108. [PubMed]
218. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511. [PubMed]
219. Mazouni C, Capo C, Ledu R, et al. Preeclampsia: impaired inflammatory response mediated by Toll-like receptors. J Reprod Immunol. 2008;78(1):80–83. [PubMed]
220. Dabbagh K, Lewis DB. Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis. 2003;16(3):199–204. [PubMed]
221. Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol. 2009;62(2):96–111. [PMC free article] [PubMed]
222. Riley JK, Nelson DM. Toll-like receptors in pregnancy disorders and placental dysfunction. Clin Rev Allergy Immunol. 2010;39(3):185–193. [PubMed]
223. Xie F, Turvey SE, Williams MA, Mor G, von Dadelszen P. Toll-like receptor signaling and pre-eclampsia. Am J Reprod Immunol. 2010;63(1):7–16. [PubMed]
224. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol. 1994;171(1):158–164. [PubMed]
225. Tinsley JH, Chiasson VL, Mahajan A, Young KJ, Mitchell BM. Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. Am J Hypertens. 2009;22(12):1314–1319. [PubMed]
226. Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of preeclampsia: systematic review and metaanalysis. Am J Obst Gynecol. 2008;198(1):7–22. [PubMed]
227. Le J, Briggs GG, McKeown A, Bustillo G. Urinary tract infections during pregnancy. Ann Pharmacother. 2004;38(10):1692–1701. [PubMed]
228. von Dadelszen P, Magee LA, Krajden M, et al. Levels of antibodies against cytomegalovirus and Chlamydophila pneumoniae are increased in early onset pre-eclampsia. BJOG. 2003;110(8):725–730. [PubMed]
229. Heine RP, Ness RB, Roberts JM. Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Obstet Gynecol. 2003;101(2):221–226. [PubMed]
230. Teran E, Escudero C, Calle A. Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Obstetrics and gynecology. 2003;102(1):198–199; author reply 199. [PubMed]
231. Abrahams VM, Schaefer TM, Fahey JV, et al. Expression and secretion of antiviral factors by trophoblast cells following stimulation by the TLR-3 agonist, Poly(I: C). Hum Reprod. 2006;21(9):2432–2439. [PubMed]
232. Koga K, Cardenas I, Aldo P, et al. Activation of TLR3 in the trophoblast is associated with preterm delivery. Am J Reprod Immunol. 2009;61(3):196–212. [PMC free article] [PubMed]
233. Nakada E, Walley KR, Nakada T, Hu Y, von Dadelszen P, Boyd JH. Toll-like receptor-3 stimulation upregulates sFLT-1 production by trophoblast cells. Placenta. 2009;30(9):774–779. [PubMed]
234. Kim YM, Romero R, Oh SY, et al. Toll-like receptor 4: a potential link between “danger signals,” the innate immune system, and preeclampsia? Am J Obstet Gynecol. 2005;193(3 pt 2):921–927. [PubMed]
235. Xie F, Hu Y, Speert DP, et al. Toll-like receptor gene polymorphisms and preeclampsia risk: a case-control study and data synthesis. Hypertens Pregnancy. 2010;29(4):390–398. [PubMed]
236. van Rijn BB, Franx A, Steegers EA, et al. Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome. PloS One. 2008;3(4):e1865. [PMC free article] [PubMed]
237. Molvarec A, Jermendy A, Kovacs M, Prohaszka Z, Rigo J,, Jr Toll-like receptor 4 gene polymorphisms and preeclampsia: lack of association in a Caucasian population. Hypertens Res. 2008;31(5):859–864. [PubMed]

Articles from Reproductive Sciences are provided here courtesy of SAGE Publications