Relationship between Maternal Immunological Response during Pregnancy and Onset of Preeclampsia
The maternal immunological tolerance to the semiallogeneic fetus becomes donors as the complete fetal genome is allogeneic to the mother. Immunological interactions between mother and child during pregnancy in relation to the development of allergic diseases in the offspring. Martina Abelius. Placentation is defined as 'any intimate apposition or fusion of the fetal organs to the maternal or paternal tissues for physiological exchange'1. It is widespread.
The Trophoblast HLA Expression Pattern The vast majority of the trophoblast that comes into contact with maternal tissue does not possess the antigenic determinants required for maternal T-cell activation; indeed it prevents the potential maternal antifetal rejection.
The syncytiotrophoblast that is the main trophoblast to come into contact with the maternal immune system lacks classic class I and II HLA antigens. EVT has an invasive phenotype and forms columns of cells that invade the maternal decidua and replace the endothelium of spiral arteries. NK cell activity is subsequently inhibited [ 24 ].
Although poorly expressed during the first trimester, its expression increases during pregnancy [ 27 ]. Like HLA-F, it can promote fetal growth as its expression coincides with the rapid fetal growth period [ 27 ]. Fas Ligand Fas-L is a transmembrane protein [ 72 ].
- Immune tolerance in pregnancy
- The maternal immune system during pregnancy and its influence on fetal development
- Journal of Immunology Research
Isolated first-trimester trophoblast cells have been described to not show FasL on their membrane but to also express a cytoplasmic form.
This intracellular FasL is constitutively secreted by trophoblast cells through the release of microvesicles. After the disruption of these microvesicles, the secreted FasL induces T-cell apoptosis through the activation of the Fas pathway [ 72 ]. This knowledge has been supported by a subsequent in vivo study, which has only found FasL production and storage in first-trimester human syncytiotrophoblast, but not in the cytotrophoblast [ 73 ].
On the other hand, it has been recently reported that the Fas-L AG polymorphism is associated with increased risk of preeclampsia [ 74 ].
Therefore, the desire to gain a better understanding of the fetal FasL expression and its contribution to maternofetal tolerance may inspire further studies. Indoleamine 2,3-Dioxygenase Indoleamine 2,3-dioxygenase IDO is an enzyme that degrades the tryptophan amino acid. It is expressed in both EVT and villous trophoblasts in humans, where it may inhibit maternal T-cell activation through the deprivation of tryptophan T-cells [ 24 ].
Immunological relationship between the mother and the fetus.
The serum tryptophan levels decrease from the first trimester of human pregnancy [ 24 ]. The pharmacological inhibition of IDO activity in murine pregnancy has been demonstrated to induce maternal T-cell-mediated rejection of the allogenic, but not the syngenic concept. Nevertheless, the genetic deletion of IDO in mice results in normal litter size as compared to IDO-sufficient control mice. It is worth noting that lack of IDO in mammals can be compensated by the tryptophan dioxygenase enzyme, which induces tryptophan catabolism [ 24 ].
The B7 Family The B7 family molecules are transmembrane proteins that belong to the immunoglobulin superfamily [ 75 ]. In order to provoke efficient T-cell activation, a positive costimulatory signal is required, which is mediated by the interaction between CD28, which is constitutively expressed in most mature T-cells, and molecules B and B exposed by APC [ 74 ]. Moreover, the frequency of B and B expressing activated monocytes in peripheral blood of preeclamptic patients is lower than in normal pregnant woman [ 77 ].
Their union provides an inhibitory signal that plays a key role in the negative regulation of the immune system [ 75 ]. Fetal tissues express CTLA-4 at the maternofetal interface during pregnancy. Susceptibility to recurrent spontaneous abortion mediated by a polymorphism in the CTLA4 gene has been suggested [ 24 ].
Another costimulatory pathway that plays a role in peripheral tolerance is defined by the programmed death-1 receptor and its ligands, PDL1 and PDL2. It is known that PDL1 is essential to maintain maternofetal tolerance, and its blockade or deficiency results in poor fetal survival and a shift toward Th1 placental cytokines [ 24 ]. Systemic Maternal Immunological Response during Pregnancy 2. Initially, it was suggested that the human fetus is not rejected by the maternal immune system due to the prevalent cytokine production of Th2 cells.
The Th2 cytokines produced at the maternal-fetal interface would inhibit Th1 responses, leading to fetal survival [ 78 ]. Yet while Th2 cells predominate in early pregnancy decidua, Th1 cells prevail in the nonpregnant endometrium, particularly in the proliferative phase. Similarly, the Th2 cytokine expression, specifically IL-6 and IL, is fold higher in the early pregnancy decidua as compared to the nonpregnant endometrium [ 80 ].
Besides, progesterone stimulates a Th2-type response, decreases inflammatory cytokines, and restrains allogeneic responses to allow fetal survival [ 18 ]. Although these cells participate in the development of humoral immunity against extracellular pathogens, they also repress the functions of phagocytic cells.
Th1 cells not only synthesize interferon-g IFN-gIL-2, and tumor necrosis factor-a TNF-but also trigger cell-mediated immunity and phagocyte-dependent inflammation [ 81 ].
A tendency for immune Th1 responses has been found in human pregnancy-related complications, such as recurrent spontaneous abortions. Significantly higher serum levels of Th2 cytokines, IL-6, and IL and considerably lower levels of the Th1 cytokine, IFN-g, have been reported in normal pregnancy as compared to unexplained recurrent pregnancy losses [ 82 ].
Accordingly, patients reporting recurrent pregnancy losses and infertile women with multiple implantation failures after IVF present increased T helper 1 cytokine responses by circulating T-cells [ 81 ]. However, the function of a major chemokine in the Th1 response, RANTES, may prove essential for modulating the responses of specific T-cells for alloantigens during normal pregnancy.
Indeed, successful pregnancies are accompanied by increased serum levels of RANTES, which are lower in patients who suffer recurrent abortions. So the high levels of progesterone present during normal pregnancy, particularly on the maternofetal surface, can be predictors of RANTES production at levels required to induce a tolerogenic immune response locally [ 18 ].
Whereas in successful pregnancies the serum levels of RANTES are high, they are low in recurrent spontaneous abortions [ 83 ]. Thus, RANTES might cooperate in the maternal tolerogenic immune response to allow trophoblast cell survival and migration [ 18 ]. Th2 preponderance in normal pregnancy shifts to Th1 predominance in preeclampsia.
In line with this, the peripheral blood mononuclear cell production of IL, which induces Th1 responses, diminishes in normal pregnant women but increases in preeclamptic patients [ 86 ]. The transcriptional regulatory protein forkhead box P3 FOXP3 is a transcriptional repressor required for the development and function of Treg cells [ 87 ].
Treg cells are essential in the induction and maintenance of MHC class II antigen-specific tolerance. It has been postulated that immature DCs, acting as APCs, catch these debris and induce peripheral tolerance through the induction of Treg cells. Treg cells also enhance the maternal tolerance of the fetus through the expression of CTLA-4 on their surface. IDO restrains the availability of tryptophan to T-cells [ 18 ]. Circulating Treg cells increase during early pregnancy, reach a higher level during the second trimester, and decline postpartum [ 91 ].
In addition, estrogen treatment and pregnancy induce a similar FoxP3 protein expression [ 87 ].
Fetal–Maternal Immunological Relationships
It has therefore been suggested that progesterone extends Treg cell populations by means of nuclear progesterone receptors. Besides, RU significantly decreases the amount and function of Treg cells at the maternofetal interface before the onset of induced abortion. The significantly reduced Foxp3 expression has been reported to be accompanied by a significant increase in proinflammatory factors [ 92 ].
Whereas the prevalence of Tregs lowered, that of Th17 cells increased in both the peripheral blood and decidua of patients with unexplained recurrent miscarriage as compared to healthy early pregnant women [ 94 ]. Interestingly, the IL expression can be inhibited by Treg. Patients with unexplained recurrent miscarriage display diminished suppressive activity of Tregs in Th17 cells when compared with healthy women who underwent early elective abortion [ 93 ]. Nowadays, it is believed that unexplained recurrent spontaneous abortions could be an alloimmune disease associated with defective maternofetal tolerance in which Treg cells play a key role.
As Foxp3 is a crucial regulatory factor for the development and function of Treg cells; Foxp3 gene deficiency suppresses the regulatory function of Treg cells.
Tregs are essential for pregnancy maintenance, and low levels have been found in pregnancy complications. Thus not only women with unexplained recurrent spontaneous abortions, but also patients with preeclampsia display low levels of Tregs in both maternal blood and placenta.
Since the complete fetal genome is allogeneic to the mother in ED pregnancies, maternofetal immune tolerance is particularly essential for pregnancy success. Strangely enough, it has been recently suggested in maternal tolerance to the semi- or allogeneic fetus in ED pregnancies that peripheral or extrathymic Treg cells are vital as they block the immune response to foreign antigens.
Conversely, thymic Treg cells suppress autoimmunity . Besides exposure to trophoblastic cell debris, exposure to sperm may also induce HLA class II-specific tolerance. Treg cells play a central role in inducing and maintaining this process [ 29 ].
Murine models have shown that Treg cells are activated by male antigens [ ]. As a matter of fact, seminal fluid expands the pool of Treg cells in the para-aortic lymph nodes draining the uterus [ ] and induces the accumulation of Treg cells in the uterus prior to embryo implantation [ ]. Indeed Treg cells are essential in embryo implantation. Treg cells accumulate in the mouse uterus in the receptive phase of the estrus cycle, and seminal fluid further promotes Treg expansion [ ].
NK cells play a key role in this tolerance induction. In pregnancies achieved by donated spermatozoa, women have not been previously exposed to semen and the fetus is a semiallograft to the mother. Since the risk of preeclampsia in donated spermatozoa is very high Along these lines, risk of preeclampsia has been studied with intracytoplasmatic sperm injection ICSI using either ejaculated sperm or surgically obtained sperm, and both cases involve exposure to seminal fluid.
In donated embryo transfer cases, the fetus is allogeneic to the mother, and no former semen exposure is involved. In such cases, risk of preeclampsia is extremely high These findings highlight the importance of sperm exposure in inducing maternofetal immune tolerance. Onset of preeclampsia may be related to the gradual decrease of Treg cells, which induce paternal antigen-specific tolerance during the third trimester of pregnancy [ 2991 ].
In addition, a protective effect of multiparity in preeclampsia has been described. Despite the possibility of memory T-cells decreasing after delivery, seminal priming may maintain their number at a certain level. Thus in a second pregnancy with the same partner, the number of memory T-cells may rapidly increase. This protective multiparity effect in preeclampsia would be lost with a change of partner [ 29 ]. It is also noteworthy that the longer the interval between second and third deliveries with the same partner, the higher the risk of preeclampsia.
This finding may be explained by the progressive decrease in memory T-cells after delivery in the second or third pregnancy. Memory T-cell levels reach their lowest levels at more than 10 years after the last delivery, and seminal priming maintains these tolerance-inducing T-cells at a low level.
Therefore, in a subsequent pregnancy, some of these women may not achieve adequate tolerance which, in turn, raises the risk of preeclampsia [ 29 ].
B Lymphocytes and Maternal Antibodies against Fetal HLA Regarding the adaptive maternal humoral immune response during pregnancy, paternal anti-HLA antibodies have been observed in multiparous mouse animal models. Similarly, fetal HLA-specific B-cells have been detected in murine pregnancies [ ]. B-cells are capable of producing antibodies [ ]. In human pregnancies, fetal antigens induce an adaptive maternal humoral immune system response. Accordingly, maternal antibodies against fetal HLA can be generated, which are especially prone to increase when the HLA mismatches between the mother and fetus are high.
Since ED pregnancies may be associated with a larger number of HLA mismatches than spontaneously conceived pregnancies, women with ED pregnancies might produce higher levels of antibodies. It remains unknown whether adverse clinical consequences occur as a result of the maternal humoral immune response to fetal antigens. American Journal of Reproductive Immunology 62 6: American Journal of Reproductive Immunology 37 6: Journal of Experimental Medicine A models of murine spontaneous abortions and prevention by leukocyte immunisation.
II selective suppression of cytotoxic cell generation correlates with soluble suppressor activity foetal—maternal immunological relationships and successful allogeneic pregnancy.
Developmental kinetics, properties, and mechanism of induction of suppressor cells during first pregnancy. Journal of Immunology 4: American Journal of Reproductive Immunology Fertility and Sterility 94 6: Biology of Reproduction Journal of Experimental Medicine 8: Immunological Investigations 37 5: Clinical and Experimental Immunology Fertility and Sterility 83 3: Human Reproduction 26 American Journal of Reproductive Immunology 63 6: Matzinger P Tolerance, danger, and the extended family.
Annual Review of Immunology Due to the rarity of this cell population, functional studies of human decidual DCs are scarce. Decidual DC—depleted mice exhibit severely impaired implantation, impaired decidual proliferation and differentiation, impaired angiogenesis, impaired differentiation of uNK cells, and resorption of embryos.
Mechanisms by which immune cells focus: These investigators demonstrated that uNK cells isolated from first-trimester human decidua express the chemokines IL-8 and IFN-inducible protein IPand that purified human invasive trophoblasts express the chemokine receptors for these ligands: The ability of uNK cells, but not peripheral blood NK cells, to induce trophoblast migration in an in vitro trophoblast migration assay was significantly reduced in the presence of neutralizing antibodies to IL-8 and IP These investigators subsequently performed in vivo studies in which NK cell subsets embedded in Matrigel were injected into the subcutaneous tissues of nude mice, and human trophoblast cells were injected around the Matrigel plug.
These in vivo experiments further demonstrated that uterine, but not peripheral, NK cells promoted trophoblast invasion, and that migration of trophoblast cells into the Matrigel plug was significantly reduced in the presence of IL and IPneutralizing antibodies.
Overall, these studies demonstrated the ability of uNK cells to positively regulate invasion of trophoblast, mediated by the uNK-derived cytokines IL-8 and IP The balance of factors involved in regulation of invasion is not yet precisely determined.Maternal immune system and fetal development – Video abstract 80652
Excessive invasion predisposes to placenta accreta, a potentially life-threatening obstetrical condition in which the placenta attaches abnormally to the uterine myometrium. Role of uNK cells in angiogenesis and vascular remodeling in early pregnancy In humans, extensive vascular remodeling must occur to allow for placentation and establishment of early pregnancy, as well as to support the demands of a growing fetus.
The decidual spiral arteries must be transformed into larger-diameter vessels with low resistance and high flow, capable of transporting nutrients and oxygen to the fetus. However, it is important to note significant differences among species in terms of strategies to increase blood flow to the site of maternal—placental exchange. In humans, extensive invasion and destruction of preexisting arteries by trophoblast occurs. In nonhuman primates such as rhesus macaques, trophoblastic invasion and modification of uterine arteries occurs, but unlike in humans, invasion of decidual stroma by trophoblast in the rhesus monkey occurs only to a minimal extent.
Nevertheless, there are in vivo studies performed in mice that cannot be performed in humans, and the availability of nonhuman primates for such in vivo studies in early pregnancy is limited. Therefore, much of the existing data on uNK cell functions in vascular remodeling are derived from murine studies. Multiple murine in vivo studies demonstrate that uNK cells play a critical role in the remodeling of endometrial spiral arteries both prior to and during pregnancy.
Multiple vascular abnormalities associated with implantation sites, including thickening of the media and adventitia, endothelial damage, reduction in placental size, and onset of fetal loss at Day 10 of gestation, were demonstrated in NK-cell-deficient mice. Subsequent studies from the same laboratory 38 demonstrated that bone marrow transplantation from severe combined immunodeficient mice which lack T- and B- lymphocytes but not NK cells to NK-cell-deficient mice led to restoration of the uNK cell population in recipients, reduced anomalies in decidual blood vessels, increased placental size, and restored fetal viability.
Overall, these studies provide strong support for a critical role of murine uNK cells in decidualization, placentation, and the appropriate vascularization of implantation sites. Rather, the finding that human uNK cells isolated from first-trimester decidua are a potent source of the angiogenic factors angiopoietin Ang 1, Ang2, VEGF, and PLGF 1633 supports an important role for these cells in the vascular remodeling required for successful human pregnancy.
Supernatants derived from human uterine but not peripheral NK cells promoted in vitro angiogenesis, as demonstrated by an increased ability of human umbilical vascular endothelial cells to form network-like structures, a process inhibited in the presence of VEGF- and PLGF-neutralizing proteins. In addition, these investigators 33 demonstrated the in vivo ability of human uNK cells to promote angiogenesis and growth of human trophoblast choriocarcinoma JEG-3 tumor cells when injected subcutaneously into nude mice.
Influence of maternal immune response on development of the fetal immune system Compelling clinical data demonstrate that children of mothers exposed to certain infectious organisms during pregnancy have significantly higher frequencies of neurological disorders, 44 — 53 including schizophrenia and autism spectrum disorders.
Rodent studies in which the maternal immune system is activated during pregnancy replicate these clinical findings and provide validated mouse models of these disorders. The underlying mechanisms of these phenomena have been studied primarily in prenatal rodent models, in which pregnant dams are injected with either infectious pathogens or synthetic agents that mimic viral or bacterial infections namely, lipopolysaccharides and polyinosinic: Offspring of such immunostimulated pregnant dams exhibit immune dysregulation and behavioral abnormalities, as well as chemical and structural anomalies of the brain, which are similar to those seen in individuals with schizophrenia and autism spectrum disorders.
In each of these models, the adult offspring of immunostimulated dams mounted a more robust inflammatory response than adult offspring of control dams injected with PBS. Our results show that mothers of autistic children in this cohort have significantly higher frequencies of proinflammatory cytokine gene polymorphisms, thereby conferring the genetic capability to respond more vigorously to immune stimulation by producing the types and amounts of cytokines that promote inflammatory reactions.
Moreover, analysis of preliminary data from the offspring indicates that the autistic children of these mothers inherit the maternal genotype. Thus, results obtained from our investigation of the experimental prenatal mouse model of maternal immune stimulation during pregnancy 73 appear to have biological relevance to humans.
Maternal—fetal tolerance Billingham et al 1 in were the first to propose the concept of immune tolerance during pregnancy. They hypothesized that the semiallogeneic fetus is able to survive due to regulation of the immunologic interactions between mother and fetus. Although there is a continuous interaction between the fetus and maternal cells throughout pregnancy, the fetus acts as a privileged site that is protected from immune rejection. In addition, extracts from Day 80 placentas from mares have been shown to inhibit proliferation of maternal lymphocytes, and coculture of trophoblast cells with maternal lymphocytes caused reduction in proliferation and cytokine production.
On the other hand, the mother must maintain sufficient immune function to fight off infection. One mechanism that plays a role in maintenance of successful pregnancy is a switch from the Th1 cytokine profile to the Th2 profile.
This switch is more prominent at the maternal—fetal interface. Therefore, Th1-type immunity appears to be controlled to avoid overstimulation during pregnancy.