Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between ‘self’ and ‘non-self’. Accordingly, the fetus activates the mother's immune system because the fetus is in part ‘non-self’. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint.Instead, the danger model suggests that normal pregnancy, regardless of the expression of ‘non-self’ antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome.Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Do double-stranded RNA receptors play a role in preeclampsia?

Dysregulation of the maternal immune system during pregnancy has been implicated in the development of preeclampsia (PE), however the pathogenetic signals and mechanisms have not been completely elucidated. Here we provide a hypothesis and evidence that dsRNA is a danger signal leading to maternal immune system activation and an “antiviral” immune response that manifests as PE. dsRNA released from necrotic cells and/or from viruses causes excessive activation of dsRNA receptors and PE-like symptoms in animals. Additionally, high expression levels of dsRNA receptors have been identified in human and animal placental tissue as well as trophoblast cells, and these receptors appear to be excessively activated in PE. These key components of the innate immune system that respond to invading pathogens and dead or necrotic tissue likely play a major role in the development of PE.     

Impaired fetal thymic growth precedes clinical preeclampsia: a case-control study

In preeclampsia the maternal adaptive immune system undergoes specific changes, which are different from the physiological processes associated with healthy pregnancy. Whether preeclampsia also affects the fetal immune system is difficult to investigate, due to limited access to the fetus. We hypothesized that if preeclampsia affects the fetal adaptive immune system this might be associated with early changes in thymic growth. In this case-control study, 53 preeclamptic and 120 healthy control pregnancies were matched for maternal age, gestational age and smoking. Fetal thymus diameter was measured as the greatest width perpendicular to a line connecting sternum and spine based on ultrasound images taken at 17-21 weeks gestation. Independent of fetal and maternal anthropometric measures, thymuses were found to be smaller in preeclamptic pregnancies than healthy controls (16.2 mm versus 18.3 mm, respectively, mean difference=2.1 mm, 95% CI: 0.8-3.3, p<0.001), and the odds of developing preeclampsia was estimated to be 0.72 (95% CI: 0.60-0.86, p<0.001) lower for each 1 mm increase in thymus diameter. There was no correlation between the onset of preeclampsia and fetal thymus size. This is the first study to suggest that fetal thymus growth is reduced before the clinical onset of preeclampsia and precedes any described fetal anomalies or maternal immunological changes associated with preeclampsia. We propose that the fetal adaptive immune system is either passively affected by maternal processes preceding clinical preeclampsia or is actively involved in initiating preeclampsia in later pregnancy.     

NLR家族Pyrin域蛋白3炎症小体与妊娠的研究进展

炎症小体是人类天然免疫系统的重要组成部分,参与包括妊娠在内的多种炎症反应,其中NLR家族Pyrin域蛋白3(NLRP3)炎症小体是目前研究最广泛的炎症小体,是宿主防御反应的重要因素,其能够对固有免疫进行调控,各种环境剌激物、多种微生物、内源性或外源性危险信号、病原体和不同的病原相关分子模式(PAMPs)/损伤相关分子模...     

Gene expression of the constant region of the heavy chain of immunoglobulin G (IgG CRHC) is down-regulated in human decidua in association with preeclampsia

An aberrant interaction at the maternal/fetal interface between the genetically distinct fetal trophoblast cells and cells of the maternal decidua has been proposed as an initiating factor in one of the major complications of human pregnancy, preeclampsia. Biochemical and epidemiological studies suggest that the immune system plays an important role in preeclampsia. Thus, the aim of this study was to determine the decidual gene expression status in preeclampsia of one of the key components of the adaptive immune system. Total RNA was extracted from decidua collected from women with normal pregnancies and those complicated by preeclampsia. Reverse Northern analysis was performed on 72 cDNAs from human decidua and differentially expressed genes identified were analysed further using semi-quantitative RT-PCR and Northern blot analysis. Expression of the gene encoding the constant region of the heavy chain of immunoglobulin G (IgG CRHC) was shown to be down-regulated in association with preeclampsia. These data support the hypothesis that immune maladaptation may play an important role in the pathogenesis of preeclampsia.     

Trophoblast deportation: just a waste disposal system or antigen sharing?

Trophoblast deportation, the removal of trophoblastic debris from the placenta via the maternal blood, was first described over 100 years ago. Deported trophoblastic debris ranges in size from nano-meter scale subcellular particles to large multinucleated syncytial knots. Whether trophoblast deportation has any biological significance remains unclear. However, the (semi) allogeneic fetus must induce maternal tolerance to paternally inherited placental antigens. We propose that the clearance of deported trophoblasts may be a mechanism by which the maternal immune system is maintained in a state of tolerance towards paternal antigens. Using an in vitro model, we have shown that when syncytial knots are shed by an apoptosis-like programmed cell death process, then phagocytosed by macrophages, the macrophages produce a tolerogenic response. However, necrotic syncytial knots, when phagocytosed, appear to be immunostimulatory. We have also shown that endothelial cells are likely to be involved in the clearance of syncytial knots from the pulmonary vessels. Phagocytosis of apoptotic syncytial knots by endothelial cells is silent while phagocytosis of necrotic syncytial knots leads to endothelial cell activation characterised by increased endothelial cell-surface adhesion molecule expression and secretion of IL-6 and TGFβ1. All of these molecules may interact with the maternal immune system to exacerbate any adverse maternal response. We propose that in normal pregnancy clearance of apoptotic syncytial knots is important to maintain maternal immune tolerance to the fetus and that in abnormal pregnancies, especially preeclampsia, clearance of necrotic syncytial knots may contribute to the pathogenesis of that condition.     

Fetomaternale Immunität

The maternal immune system has to fulfill several tasks during pregnancy. On the one hand it has to protect both mother and fetus from infection, and on the other it has to prevent the rejection of the fetus and its extrusion of tissue antigens from both the mother and father. Due to this, maternal immunity changes during pregnancy, particularly the adaptive immune system (T lymphocytes). Active induction of T helper (Th) 2 function occurs at the fetomaternal barrier. Cells in the decidual tissue play an important role in the regulation of this reorientation and support the changes in maternal immunity. These maternal influences induce an effective and functional maturation of the lymphocyte system in the fetus. From the 20th week of pregnancy, the fetal lymphocyte system is fully developed and is able to be confronted with diaplacental transport of antigens. Fetal antigen contact is important for developing immunological tolerance against environmental antigens (e.g., foods) which have to be tolerated immediately after birth. Recently, a number of experimental data have been published. The following article gives a survey of these data.     

Peripheral blood invariant natural killer T cells throughout pregnancy and in preeclamptic women

Invariant natural killer T (iNKT) cells are implicated in the pathogenesis of several diseases. They influence both innate and adaptive immune responses through their capacity to rapidly produce large quantities of cytokines upon activation. During pregnancy maternal immunity is biased towards type 2 cytokine production to regulate type 1 cytokines that could be harmful for the developing fetus. This shift to type 2 cytokines does not occur in preeclamptic women and there is an exaggerated maternal inflammatory response which is dangerous for both mother and baby. We have therefore investigated the numbers, phenotype and functional activity of iNKT cells throughout pregnancy and in women diagnosed with preeclampsia. We demonstrate that the numbers of iNKT cells in the peripheral blood do not change between the first, second and third trimesters of pregnancy, but the cells become activated and less able to produce the type 1 cytokine IFNγ. However, iNKT cells are unchanged in preeclamptic women, when compared to normal pregnancy, suggesting that these cells are not primary players in the pathogenesis of the disease.     

Immunological tolerance of the human fetus

Why is the fetus not rejected as foreign tissue? The maternal and fetal immune systems temporarily coexist; both are precisely tuned to detect and reject foreign invasion and yet somehow achieve a symbiotic relationship. This mutual state of tolerance is obviously critical for carrying pregnancy to full term. Two active arms of the immune system maintain protection of the host: the first of these involves a humoral immune system in which foreign tissue invokes an antibody response by recognition of antigenic surfaces by the B-cell, the second arm involves cell-mediated immunity in which T-cells and natural killer (NK) cells seek out and destroy foreign tissue. Several mechanisms are thought to invoke the immune tolerance of the fetus. These include: absence of major histocompatibility complex (MHC)-I antigens, presence of unique human lymphocyte antigen (HLA) surface molecules, nonspecific reduction of systemic immunoreactivity, possible role of blocking antibody, expressions of complement regulatory proteins, and factors of locally reduced immunoreactivity. Ultimately, developing regimens to control these elements in the clinical setting may help us overcome preterm labor, infertility, and preeclampsia. Available evidence regarding immune tolerance of the human fetus, integrated into a workable model, and focused at an overview level are systematically reviewed in this article.     

Association between gamete source,exposure and preeclampsia: A review of literature

Preeclampsia complicates 3%-5% of pregnancies and is one of the major causes of maternal morbidity and mortality. The pathologic mechanisms are well described but despite decades of research, the exact etiology of preeclampsia remains poorly understood. For years it was believed that the etiology of preeclampsia was the result of maternal factors, but recent evidence suggests that preeclampsia may be a couple specific disease where the interplay between both female and male factors plays an important role. Recent studies have suggested a complex etiologic mechanism that includes genetic imprinting, immune maladaptation, placental ischemia and generalized endothelial dysfunction. The immunological hypothesis suggests exaggerated maternal response against fetal antigens. While the role of maternal exposure to new paternal antigens in the development of preeclampsia was the initial focus of research in this area, studies examining pregnancy outcomes in pregnancies from donor oocytes provide intriguingly similar findings. The pregnancies that resulted from male or female donor gametes or donor embryos bring new insight into the role of immune response to new antigens in pathogenesis of preeclampsia. The primary goal of the current review is the role of exposure to new gametes on the development of preeclampsia. The objective was therefore to provide a review of current literature on the role of cohabitation length, semen exposure and gamete source in development of preeclampsia.     

Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response

Preeclampsia is characterized by generalized endothelial dysfunction as a result of an inappropriate maternal immune response against the fetus. It has been postulated that the adaptive immune system plays a key role in the etiology of preeclampsia by generating a pro-inflammatory Th1 type immune reaction. In this review, recent studies on Th1 and Th2 type cytokine mapping in preeclampsia are reviewed, as well as on the sources of pro-inflammatory cytokines and the role of regulatory cytokines and chemokines. In addition, we discuss the possible role of Toll-like receptors of the innate immune system in the pathophysiology of preeclampsia. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the newer concepts related to the pathogenesis of preeclampsia and explain the role of the maternal immune system and the role of pro-inflammatory and regulatory cytokines and chemokines in the pathophysiology of the disease.     

Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance

Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., “immunological noise”). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of “self” (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.     

NK cells and pre-eclampsia

The immunological interaction between the mother and fetus has classically been thought of as one between paternal antigen and maternal T cells. However, the MHC antigen expression on human trophoblast and the immune cell populations present in the decidua suggest that this interaction primarily involves decidual NK cells rather than T cells, and this is supported by new functional studies. It is becoming apparent also that the maternal systemic immune response in pregnancy (Th1/Th2 shift) primarily involves NK cells. Aberrant NK cell activation both locally in the decidua and systemically in the maternal blood may be the cause of pre-eclampsia.     

Altered dendritic cell function in normal pregnancy

In pregnancy, maternal immunity is skewed to favour maintenance of gestation and immune tolerance of a semi-allogeneic fetus. Dendritic cells are thought to play a crucial role in mediating the balance between immunity and tolerance, and determining the type of T helper cell response. We postulated that myeloid dendritic cells would be modified in pregnancy to favour type 2 T helper cell responses. We show that the proportion of circulating myeloid dendritic cells expressing CD86 and staining for HLA-DR were significantly lower in the third trimester of pregnancy compared with non-pregnant women. As pregnancy progressed through the third trimester to term, CD86 expression increased. Furthermore, monocytes from pregnant women differentiated into less phenotypically mature dendritic cells which expressed lower levels of CD80, CD86 and HLA-DR molecules compared with non-pregnant women. In response to inflammatory stimuli, monocyte-derived dendritic cells, from pregnant women up-regulated CD86 more than CD80, and secreted less IL-12p70 but more IL-10, compared with monocyte-derived dendritic cells from non-pregnant controls. Our results demonstrate that, in pregnancy, the dendritic cell system is modified to favour type 2 T helper cell responses.     

Preeclampsia,insulin signalling and immunological dysfunction: a fetal,maternal or placental disorder?

An inappropriate glycogen accumulation in preeclamptic placentas was described as secondary to biochemical alterations. Insulin resistance is widely accepted to be associated with preeclampsia, although its basis remain unclear. A family of putative insulin mediators, namely inositol phosphoglycans, were described to exert many insulin-like effects on lipid and glucose metabolism. A definite association between the P-type mediator (P-IPG) and preeclampsia was reported, being increased in placenta, urine, amniotic fluid and cord blood from human preeclamptic pregnancies. A strong link exists between insulin resistance and inflammation. Clear features of insulin resistance and systemic inflammatory activation were described in preeclampsia. It may be a consequence of the immunological dysfunction that occurs in preeclampsia that is temporized during sperm exposure and co-habitation which confuses the maternal immune network to perceive ‘danger’. The over-expression of P-IPG during preeclampsia may be a counter-regulatory mechanism to insulin resistance since these molecules mimic insulin action. Besides, the lipidic form of P-IPG was reported to be similar to endotoxins, and may represent the ‘danger signa’. We propose here a novel working theory on insulin resistance and preeclampsia.     

Nonspecific immunity in pregnancy: monocyte surface Fcγ receptor expression and function

The state of pregnancy is an immunological enigma during which the body must prevent rejection of the antigenically foreign fetus while at the same time maintain sufficient maternal host defense mechanisms to combat infection. Although most studies on the immunology of pregnancy focus on immune suppression, several studies have shown an increase in nonspecific host defense, which is postulated to be a compensatory mechanism for decreased specific immunity during pregnancy. Studies in this laboratory have shown that monocyte surface FcγRI (CD64) and FcγRII (CD32) expression progressively increase throughout pregnancy, while surface MHC class II expression remains unchanged. Functional studies revealed that the number of phagocytic monocytes which could be isolated from pregnant women was increased. These cells exhibited an increased capacity to ingest IgG-opsonized human erythrocytes. This study shows for the first time that monocyte surface FcγR expression and FcγR-mediated functions are increased during pregnancy. These results support the hypothesis that nonspecific immunity as represented by FcγR expression and function is increased during pregnancy.     

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

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

Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance

It is still not understood how the fetus escapes from being attacked by the maternal immune system. Recent reports based on mouse and in vitro models have suggested that the enzyme indoleamine 2,3-dioxygenase (IDO) is important for materno-fetal tolerance. IDO activity in the human placenta is known to be high and might lead to inhibition of T-cell proliferation, thus preventing fetal tissue from rejection by the maternal immune system. In an attempt to elucidate the precise location of IDO at the feto-maternal junctional zone, we investigated human placental and decidual tissue of first and third trimester of pregnancy using an immunohistochemical approach. In placental tissues, only syncytiotrophoblast and endothelial cells showed moderate expression of IDO. This pattern was observed regardless of whether first or third trimester tissue was investigated. In early and term decidua, cells with the typical morphology of invasive extravillous trophoblast (EVT) were strongly positive for IDO. Blocking immunohistochemical experiments with cytokeratin and IDO antibodies identified invasive EVT as the location of predominant IDO expression. Since EVT are the fetal cells with the closest contact to the maternal immune system, our results suggest that it is EVT which protects the fetus from rejection by downregulating local maternal T-cell responses.