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Immunology of the maternal-fetal interface

Immunology of the maternal-fetal interface
Author:
Vikki M Abrahams, PhD
Section Editors:
Rebecca Marsh, MD
Charles J Lockwood, MD, MHCM
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jan 2023. | This topic last updated: Apr 06, 2021.

INTRODUCTION — In pregnant females, local adaptation of the maternal immune system allows for successful coexistence between the mother and the semi-allograft that is the fetus/placenta expressing both maternal (self) and paternal (nonself) genes [1-4]. Cytotoxic adaptive immune responses are diminished, bypassed, or even abrogated, while regulatory adaptive immunity is enhanced [5,6]. By contrast, innate (natural) immunity remains intact, serving two purposes: one, to continue to provide host defense against infection, and two, to interact with fetal tissues to promote successful placentation and pregnancy [4,7-10].

An introduction to the immunology of pregnancy and the maternal-fetal interface is presented in this topic review. Basic immunologic concepts are reviewed separately. (See "An overview of the innate immune system" and "The adaptive cellular immune response: T cells and cytokines".)

IMMUNE DEFENSE MECHANISMS OF THE PLACENTA AND EXTRAPLACENTAL MEMBRANES — The placenta and fetal membranes are directly exposed to maternal blood and tissues. Thus, unique features of the cells that comprise this interface must underlie the remarkable ability of the genetically distinct fetal tissue to inhabit the maternal host.

Many immunologists studying reproduction agree that maternal immunity is not solely antagonistic to trophoblast tissue [11,12]. Indeed, a maternal immune presence in the decidua is essential for successful implantation [4]. Evidence of the opposite hypothesis (ie, that trophoblasts have offensive mechanisms for actively killing maternal lymphocytes) is lacking. It is clear, however, that the placenta is normally protected from the killing functions of maternal cells through a number of immune-protective mechanisms [13].

Fetal trophoblast cells — Fetal trophoblast cells are the specific cell layer that protects the embryo from those components of the maternal immune system dedicated to destroying foreign tissues. The inner cell mass and resultant embryo are secluded and protected beneath a layer of trophoblastic cells throughout pregnancy (figure 1).

Trophoblast cells are derived from the external trophectoderm layer of the blastocyst and develop into the placenta. Precursor trophoblast cells choose one of three developmental pathways (see "Placental development and physiology" and "The placental pathology report"):

●They may remain quiescent in the villi as a pool of cells for future needs (villous cytotrophoblast cells).

●They may proliferate and migrate/invade into the decidua, ultimately forming the chorion membrane (extravillous cytotrophoblast cells). Extravillous trophoblast cells may also interact with maternal decidual immune cells and invade into the maternal spiral arteries, replacing the endothelial layer (endovascular trophoblast).

●They may merge into the developing syncytiotrophoblast through a process of cell fusion to create a multinucleate cell layer. While this creates a barrier for the controlled movement and transport of molecules, the placenta is not an impermeable barrier. There is evidence for the bidirectional movement of maternal and fetal cells [14]. This may be explained, in part, by the presence of gaps in the syncytiotrophoblast, particularly later in gestation [15].

These subpopulations of trophoblasts are variably exposed to maternal hematopoietic elements in the decidua (extravillous cytotrophoblast cells, chorion membrane cytotrophoblasts, and endovascular trophoblasts) and in maternal blood either flowing over the fetal surface of the placenta (syncytiotrophoblasts) or within the spiral arteries (endovascular trophoblasts). Certain trophoblast cells (villous cytotrophoblast cells) are only rarely exposed to maternal blood.

Placental membranes — The placenta and its attached membranes can protect themselves from maternal immune cell attack and modulate the local maternal immune system to promote and maintain normal placentation and pregnancy. The mechanisms utilized vary with the state of differentiation and anatomic location of the trophoblast cells. This cell type, which protects the embryo itself as well as certain components of the extraembryonic membranes that are derived from the inner cell mass, such as the amnion membrane, relies upon multiple strategies to avoid detection by potentially cytotoxic maternal immune cells and antibody-mediated cell destruction while influencing the local immune environment that is necessary for successful pregnancy [4].

Specific immune-protective mechanisms

Altered expression of HLA and related molecules — The primary cellular immune response that develops against transplanted tissue is directed against the major histocompatibility complex (MHC) proteins on donor tissue [16]. In humans, the MHC proteins are called human leukocyte antigens (HLAs).

The placenta is not a typical transplant, since proteins derived from HLA genes are not expressed codominantly on trophoblast cell membranes, unlike other cell types. (See "Human leukocyte antigens (HLA): A roadmap" and "Transplantation immunobiology".)

●HLA class I – Strict regulation of the expression of specific HLA class I molecules in subpopulations of trophoblasts is believed to protect the fetus against maternal immune cells programmed to attack cells expressing foreign (paternal) HLA class I antigens. The extravillous trophoblasts migrating into the decidua lack expression of HLA-A or HLA-B class Ia antigens that are primary stimulators of classical graft rejection and instead display a unique pattern of class Ia HLA-C and the nonclassical HLA class Ib molecules, HLA-E, HLA-F, and HLA–G [1,17,18]. The genes encoding HLA-E, HLA-F, and HLA–G antigens have few alleles in comparison with HLA-A and HLA-B. HLA-G, HLA-C, and HLA-F are expressed by first trimester extravillous trophoblast, and, as gestation proceeds, their expression weakens and becomes intracellular. HLA-E is expressed by the extravillous trophoblast only in the first trimester [17].

HLA-C, HLA-E, HLA-G, and HLA-F may act to dampen or modulate maternal immune responses by interacting with killer immunoglobulin-like receptors (KIRs) on decidual NK (dNK) cells, macrophages, and a subset of T cells and with the T cell receptor on CD8+ T cells [1,18-21]. The consequences of these interactions include activation of pathways in NK cells and macrophages that interfere with the killer functions of these cells [22,23]. At the same time, HLA-E and HLA-G may activate pathways in dNK cells, macrophages, and T cells that promote trophoblast migration and placentation [18,24].

One mechanism by which HLA-G influences dNK cell and T cell function is through a process of trogocytosis, in which a lymphocyte transfers plasma membrane fragments containing cell surface molecules from an antigen-presenting cell to its own surface via the immunologic synapse [18]. These acquired HLA-G+ NK and T cells are immunosuppressive [25]. The HLA class Ia antigen, HLA-C, is expressed on extravillous trophoblast and may have important interactions with leukocytes in some mothers [1,26]. As an example, certain combinations of maternal KIRs and fetal HLA-C variants correlate with low birth weight and preeclampsia [27,28]. HLA-C expression may be regulated by Nod-like receptor family pyrin domain-containing 2 (NLRP2) [29].

HLA-G mRNA can be alternatively spliced to yield membrane-bound and soluble variants. Soluble HLA-G is associated with immunomodulatory functions and promotion of placentation [18,30]. Antigen-presenting cells expressing either a soluble or membrane-bound form of HLA-G repress T cell alloproliferation via this pathway [31]. Soluble HLA-G (HLA-G5) has been identified in maternal serum, is biochemically unique among the HLA-G isoforms, and is associated with specific immune modulation and the promotion of a pro-placentation environment [32-36].

In contrast to migrating extravillous cells, syncytiotrophoblast forming the outermost layer of the placental villi that is exposed to maternal blood does not express membrane-bound HLA class I antigens [37]. Syncytiotrophoblast in term placentas lacks HLA class IA mRNA (HLA-A, HLA-B, and HLA-C) and membrane-bound protein [1,18-20]. However, there is evidence for HLA class IB (HLA-E, HLA-F, and HLA-G) mRNA and antigens in this continuous cell layer both early and late in pregnancy [1,18,33,38,39].

●HLA class II – The genes that encode potentially dangerous paternally derived foreign HLA class II HLA-D region molecules are entirely repressed in trophoblast cells. None of the trophoblast subpopulations express HLA class II antigens either in vivo or in vitro. Control over transcription of class II genes may be exerted by silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and interferon (IFN) gamma-inducible MHC class II gene transcription [40].

●B7 family – Members of the B7 family of costimulatory molecules that have both lymphocyte stimulatory and inhibitory functions are expressed on trophoblast cells in human placentas and may play a critical role in maintaining tolerance to the fetus. The B7H1 protein (programmed death ligand 1 [PD-L1]; CD274), which has lymphocyte inhibitory properties, is expressed on syncytiotrophoblast and, therefore, positioned to interfere with activation of lymphocytes circulating in maternal blood. Interactions between villous and extravillous trophoblast PD-L1 (B7H1) and programmed cell death protein 1 (PD-1; CD279) expressed by maternal lymphocytes promote T regulatory (Treg) cell development and function and inhibit activated T cells (T helper cell type 17 [Th17] cells) [41-43].

●IDO – Trophoblast cells produce indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan by promoting its catabolism. This is believed to inactivate T cells since they require tryptophan. Although IDO is clearly important to survival of the mouse embryo, studies in IDO-/- knockout mice have failed to reveal any impact on pregnancy [44]. Evidence is beginning to emerge in support of this potential mechanism in humans [45].

●TNF superfamily – Apoptosis-inducing members of the TNF supergene family may also have important roles in protecting the placenta and its membranes by inducing apoptosis in potentially cytotoxic T cells. The ligands identified in and/or on human trophoblasts include TNF-alpha, FasL, and TRAIL, as well as a number of less well-characterized TNF superfamily members [46-49]. Some of these latter ligands, which include B cell-activating factor (BAFF), may positively influence pregnancy host defenses by supporting maternal and/or fetal antibody production [50].

All of these molecules, which are expressed as both membrane and soluble forms, can kill activated immune cells targeting the trophoblast by transducing an apoptotic signal via specific receptors on activated leukocytes. FasL may be of particular importance since FasL prevents immune cell attack by interacting with leukocyte receptors (eg, Fas) in other organs such as the eye and the testis.

●Microparticles – Placental-derived microparticles, such as microvesicles and exosomes that contain an array of placental proteins, mRNA, and microRNAs, are thought to play a role in regulating the maternal immune system during pregnancy. Studies have shown that the trophoblast secretes active FasL via exosomes and microvesicles [51,52]. Some B7 family members, as well as HLA-G, can also be released from the placenta via exosomes [53]. The release and content of these microparticles are increased and/or altered under certain pathologic conditions, and, as such, they may be involved in the pathogenesis of pregnancy complications such as preeclampsia [54-57]. Exosome-mediated transfer of placental-specific microRNAs regulates trophoblast and maternal cell immunity to viral infections [58]. A novel mechanism by which maternal immune cells can signal to the placental unit via exosomes has been proposed [59].

Soluble immunomodulators — Maternal immune modulation during pregnancy may also be conferred by the synthesis of immunosuppressive or immunoregulatory molecules. As examples, the human placenta produces progesterone, prostaglandin E2 (PGE2), and antiinflammatory cytokines such as interleukin (IL) 10 and IL-4 [1,19,20,60,61]. Progesterone may drive placental production of these antiinflammatory cytokines in placental cells just as it does in lymphocytes. For example, IL-10 appears to stimulate production of HLA-G [62], and dysfunction of this pathway may be important in preeclampsia [63]. Studies using IL-10-/- knockout mice have highlighted the potentially important protective role for this cytokine in pregnancy [64]. Soluble thymic stromal lymphopoietin (TSLP) may also play a role. TSLP secreted by trophoblast cells stimulates decidual dendritic cells (dDCs) to produce IL-10 and chemokine (C-C motif) ligand 17 (CCL17) [65]. These activated dDCs induce T helper cell type 2 (Th2) differentiation of decidual T cells. Lower levels of TSLP are seen in miscarriage than in normal pregnancy.

Complement proteins — Trophoblast cells express high levels of the following complement regulatory proteins: CD46 (membrane cofactor protein [MCP]), CD55 (decay accelerating factor [DAF]), and CD59 (membrane inhibitor of reactive lysis [MIRL]) [66,67]. Complement regulatory proteins are critically important for protecting the extraembryonic tissues from maternal antipaternal cytotoxic antibodies since complement activation leads to opsonization and destruction of the immunologic target (the fetal cells). (See "Regulators and receptors of the complement system".)

Mothers routinely produce high titers of antibodies to paternally derived HLA and unique trophoblast antigens, such as the unique placental isoform of alkaline phosphatase. Antibody induction of complement-mediated lysis is prevented by high expression of CD46 and DAF in various subpopulations of trophoblast cells.

Evidence supporting a role for complement proteins in placental immune protection is provided by genetic deletion experiments. In mice, the absence of the complement regulatory protein derived from Crry gene leads to placental disruption due to complement deposition in the placenta and lysis of cells at the implantation site, followed by a massive inflammatory reaction and fetal demise [68].

LOCAL IMMUNE ADAPTATION IN THE PREGNANT UTERUS — Dramatic changes take place in the uterus during pregnancy that also help contribute to immune acceptance of and/or crosstalk with the fetus/placenta to promote a successful pregnancy.

Differences in lymphocyte populations — The first histologically apparent maternal immunologic adjustment to the embryo is a dramatic change in the relative proportions of leukocyte subpopulations in the uterus. The endometrial natural killer (NK) cell population shifts from uterine NK (uNK) cells to decidual NK (dNK) cells (CD56brightCD16-), and this phenotype is distinct from both CD56bright and CD56dim peripheral blood NK (pNK) cells [69]. The origin of dNK cells remains controversial as it is unclear whether these cells are recruited from the periphery, if the local environment drives their unique phenotype, or both. Furthermore, their function is thought to be distinct given that many genes, including some with immunomodulatory properties, are overexpressed in dNK cells when compared with their peripheral counterparts [69]. Invading fetal trophoblasts become admixed with dNK cells, macrophages, and dendritic cells that account for approximately 70, 20, and 2 percent, respectively, of all cells in the decidua [70-72]. In addition, the uterine T cell population during pregnancy expands across gestation and is mostly regulatory in nature [73].

Decidual macrophages exhibit phenotypic elasticity, adapting to the local microenvironment. During the peri-implantation period, decidual macrophages display an M1 (inflammatory) phenotype. During the period of placentation, there is a mixture of M1 (inflammatory) and M2 (antiinflammatory) decidual macrophages, which shift to predominantly M2 after placentation [74,75]. The placenta may promote this via secreted factors [76]. At parturition, there is an accumulation of M1 decidual macrophages [74,75]. There are also subsets outside of conventional phenotyping [74,77]. While decidual macrophages may help to prevent uterine infections in pregnant females, some studies suggest that trophoblast-macrophage crosstalk is more important for promoting normal placentation by being involved in implantation, placental development, immunoregulation, vascular remodeling, and tissue homeostasis [9,76,78-80]. Aberrant macrophage numbers and activation may play a role in pregnancy complications, such as preeclampsia, intrauterine growth restriction (IUGR), or preterm birth [9,81,82]. Macrophages are also present throughout gestation in the placental villi and are known as Hofbauer cells. These fetally derived immune cells also display a M2 phenotype, although they can generate strong inflammatory responses to infectious triggers. Hofbauer cell numbers are also altered in pregnancy complications such as preeclampsia and chorioamnionitis [83-85].

Similarly, the major roles of dNK cells may also be unique to pregnancy [86]. Although dNK cells express a high level of cytotoxic factors, they are unable to form cytotoxic synapses to deliver granule contents [87] and instead appear to play a role in trophoblast attraction and invasion, decidual and placental angiogenesis and possibly fetal vasculogenesis, and vascular modifications in the uterus [88-91]. A population of uNK cells that are found in repeated pregnancies has been identified. These "memory-like" uNK cells may be involved in promoting placentation [92]. One study proposed that uNK cells maintain endometrial homeostasis by clearing senescent decidual cells [93]. As with macrophages, alterations in dNK cell numbers and activation status may play a role in pregnancy complications, such as immunologic infertility, recurrent spontaneous abortion, and preeclampsia [27,28,94-98]. Excessive dNK cell recruitment and/or expansion, as well as elevated cytotoxic activity, have been associated with pregnancy disorders such as implantation failure and miscarriage [97]. However, some studies suggest the opposite that deficiencies in uNK numbers are associated with recurrent pregnancy loss, highlighting the need to reassess approaches to NK cell profiling in patients with adverse outcomes [99,100]. NK cell depletion compromises pregnancy in mice, further underscoring their importance during pregnancy [101].

Innate lymphoid cells (ILCs) distinct from NK cells have been characterized in the human decidua. During early pregnancy, group 3 ILCs (ILC3) are found. While their function is not fully understood, ILC3s may establish functional interactions with stromal cells, regulate the recruitment and function of other maternal immune cells, and contribute to vascular remodeling [102,103]. At term, both ILC2s and ILC3s have been found in the decidua, and levels may increase in preterm birth [104].

The role of decidual dendritic cells (dDCs) is less clear, although mouse studies have demonstrated that these cells are critical for successful implantation and may also be involved in remodeling of the maternal vasculature [6,105,106]. However, alternative views exist. One is that dendritic cells may promote systemic immune tolerance during pregnancy [107]. Another is that dendritic cells are trapped in the decidua to prevent the exposure of peripheral T cells to fetal antigens [108]. Uterine dendritic cells are also thought to contribute to pregnancy success by influencing NK cell function and the cytokine profile at the maternal-fetal interface [109]. Depletion of uterine dendritic cells in mice results in a severe impairment of implantation and embryo resorptions, highlighting their importance [106]. Preeclampsia is also associated with persistence of decidual basalis macrophages and recruitment of dendritic cells [110,111]. One hindrance of our understanding of the presence and function of dendritic cells at the maternal-fetal interface is that there are many subpopulations, and there is a lack of comprehensive phenotyping. However, new immunophenotyping approaches are emerging [112].

Gamma-delta T cells and a population of double-negative T lymphocytes (CD4-/CD8-) have been reported in pregnant uteri [113,114]. Their roles are unclear, although immunosuppressive gamma-delta T cells may play a role in regulating the maternal immune system to protect the maternal-fetal interface from aggressive immune responses [115,116]. Increased numbers of gamma-delta T cells may be associated with pregnancy loss [116]. It was once thought that CD8+ effector T cells in normal pregnancy were eliminated from or prevented from entering the maternal-fetal interface. However, studies have suggested that there is a population of highly differentiated CD8+ effector memory T cells within the pregnant decidua. The antigenic target of these cells is still unclear, as is their function and whether they are protective [117-119].

CD4+CD25+ regulatory T cells (Tregs) are also present in the decidua of normal pregnant females, and their presence and expansion during pregnancy are thought to be triggered in both alloantigen-dependent and alloantigen–independent manners [5,120,121]. In human cocultures of HLA-G+ extravillous trophoblast cells and CD4+ T cells, there is an increase in the number of cells expressing a Treg phenotype [122]. These fetal-specific Tregs persist after delivery and rapidly reaccumulate during subsequent pregnancies, indicating a memory response [123]. In a mouse model, increased numbers of Tregs are seen in response to an antigenic fetus [124]. Selective killing of these Tregs results in fewer antigenic offspring. There are decreased numbers of peripheral blood and decidual Treg cells in females with preeclampsia compared with normal pregnancy subjects. These findings suggest that Tregs play a role in maternal tolerance to the fetus [121,125,126].

A subpopulation of CD4+ interleukin (IL) 17-producing T cells (T helper cell type 17 [Th17]) have also been described in pregnancy. Their numbers are also expanded in the pregnant uterus, although not as much as CD4+CD25+ Tregs. While they are inflammatory in nature, the presence of Th17 cells may play a role in protecting the maternal-fetal interface from microbes, and the Tregs present may serve to regulate their function. Thus, altered numbers of Th17 and/or ratio of Th17 to Tregs are associated with pregnancy complications, such a spontaneous abortion, preeclampsia, and preterm birth [121,127].

Mast cells are classically associated with allergic immune responses. However, in pregnancy, their presence in the decidua may contribute to successful placentation. Uterine mast cells expand in early pregnancy in the mouse [128] and are higher in human pregnancies compared with nonpregnant females [129]. In the mouse, they have been shown to promote an antiinflammatory state and contribute to tissue remodeling, angiogenesis, and spiral artery transformation [128].

A subset of IL-10-producing regulatory B cells (CD19+CD5+CD1d+) has been shown to expand peripherally in mice and humans during pregnancy. In abortion-prone mice, expansion of these regulatory B10 cells is not seen, and fetal rejection can be prevented by adoptive transfer of these cells from normal pregnant mice [130,131]. While the presence of CD19+ B cells in the human decidua throughout pregnancy has been reported [132,133], the importance of regulatory B cells in the human decidua remains to be determined.

Soluble immunomodulatory agents — Uterine immune regulation is also provided by the induction of immunomodulatory molecules that permeate the uterine environment. These principally include progesterone, prostaglandins, and some cytokines.

Progesterone — Progesterone, the dominant hormone of pregnancy, is initially produced by the corpus luteum. Subsequently, the placenta is responsible for almost all progesterone synthesis.

High concentrations of progesterone can suppress the maternal immune response [134]. As an example, progesterone alters the T helper cell type 1 (Th1)/T helper cell type 2 (Th2) balance and inhibits production of tumor necrosis factor (TNF) alpha in both mouse and human macrophages [135,136].

Prostaglandin E2 — Prostaglandin E2 (PGE2) is produced by resident macrophages and decidual cells. Lymphocytes proliferate poorly in the presence of this compound.

Cytokines — High levels of Th2-type cytokines are typical of mouse pregnancy [137,138] but are less definitive in pregnant females. Nonetheless, many still consider human pregnancy to be a Th2 antiinflammatory condition and that a shift towards Th1 cytokines will lead to abortion or pregnancy complications. As an example, elevated levels of IL-6 in cervicovaginal and amniotic fluid, but not plasma, was associated with spontaneous preterm birth [139]. Similarly high levels of proinflammatory IL-1-beta and TNF-alpha in the amniotic fluids are associated with preterm birth [140,141]. While disruption in cytokine profiles during pregnancy may be detrimental, it is important to appreciate that human pregnancy is both proinflammatory and antiinflammatory, depending upon the stage of gestation, rather than focusing on the murine Th1/Th2 terminology [4,120,142]. What is clear is that the appropriate balance of cytokine and chemokine expression at the maternal-fetal interface can govern the immune cell profile and function within the decidua. For example, one study demonstrated in mice that effector T cells cannot accumulate within the decidua, in part because of the epigenetic silencing of key chemokine genes in decidual stromal cells [143]. In contrast, the expression of specific cytokines and chemokines by the decidua and placenta are critical for recruitment and maintenance of pro-pregnancy immune cells [144].

MATERNAL SYSTEMIC IMMUNE RESPONSES — The pregnant immune system bears markers of both immune activation and dampening. However, the consensus is that there is no generalized immunosuppression of maternal immune responses in pregnancy. However, selective suppression or modulation may occur. Studies have reported a decrease in proinflammatory capacity with dampening of the response to microbial stimulation, while others have reported more monocyte-derived interleukin (IL) 12 in response to lipopolysaccharide (LPS) [145-149], for example. Thus, it appears that skewing adjusts the maternal response to microbial challenge rather than effecting a global suppression. In addition, the release of placental-derived microparticles may play a key role in systemic maternal immune regulation [54-56].

Although multiparous females are excellent sources of antibodies to paternal human leukocyte antigens (HLAs), maternal B lymphocytes specific for paternal HLA are partially deleted during pregnancy. In addition, T lymphocytes specific for paternal HLA are difficult to demonstrate. Results in transgenic mice suggest that pregnancy selectively depresses maternal T cells that recognize paternal H-2 class I histocompatibility antigen [150]. (See "The adaptive humoral immune response".)

There are at least two mechanisms for overcoming most immune reactions: One is active suppression, and the other is enhanced tolerance. Enhanced tolerance has been clearly demonstrated in normal pregnancy. Regulatory T cells (Tregs), which are critical mediators of tolerance, become more numerous in pregnancy in response to the introduction of fetal (paternal) antigens [151-154]. These Tregs produce IL-10, which appears to play a role in maintaining pregnancy. In animals, IL-10 blockade increased the rate of abortions, although successful pregnancy was still possible [155,156]. A population of IL-10 producing CD19+CD24hi CD27+ regulatory B cells expands during normal pregnancy, and their role may be to suppress undesired immune responses from maternal T cells [157].

IMMUNE FACTORS IN EARLY PREGNANCY LOSS — A high number of potential pregnancies are lost prior to or during implantation, based upon the identification of chorionic gonadotropin (human growth hormone [hCG]) in females. Spontaneous miscarriage before 20 weeks of gestation affects 15 to 20 percent of pregnant females in the US [158]. While approximately 60 percent of miscarriages can be accounted for by chromosomally abnormal embryos, the remainder are idiopathic [158] and, in many cases, are thought to arise from implantation failure [159]. Whether any of these losses can be accurately attributed to an immunologic cause (ie, based on maternal recognition and rejection of normal embryos expressing paternal antigens) remains unclear despite research. In contrast, recurrent embryonic losses due to genetic and endocrine abnormalities are well documented, as are miscarriages due to infection and antiphospholipid antibodies. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Causes of female infertility".)

Implantation and maternal immune rejection — Programming the uterus for successful implantation of the semiallogeneic pregnancy may occur with the introduction of semen, which contains not only paternal antigen but immunomodulatory factors, such as prostaglandin E2 (PGE2) and transforming growth factor (TGF) beta [160]. Subsequently, assuming that the implanted blastocyst is intact and fully competent to develop into a fetus, the embryo should be entirely protected by trophoblasts via the proposed mechanisms previously described. However, in some females in whom the blastocyst is genetically abnormal, exposed paternally derived antigens may be detected, resulting in a graft rejection response. A secondary immune response would be expected to cause early rejection in cases of recurrent spontaneous abortion.

Alternatively, some mothers with recurrent spontaneous abortions may lack essential components of the described networks that provide immunologic protection to the embryos.

The most well-described immunologic dysregulation in females with infertility and recurrent pregnancy losses (RPL) is related to natural killer (NK) cell numbers and function. In general, excessive uterine NK (uNK) cell recruitment and/or expansion, as well as elevated cytotoxic activity, are associated with implantation failure and RPL. Similarly, altered peripheral blood NK (pNK) cells populations may also correlate with pregnancy losses and are a potential diagnostic marker [97]. Consequently, there have been efforts targeting NK cells in an attempt to cure infertility and miscarriage; however, well-controlled trials are lacking [161,162]. Alterations of the T helper cell type 17 (Th17)/regulatory T cell (Treg) ratio both locally at the maternal-fetal interface and systemically are also associated with RPL [97], as are elevated levels of peripheral blood myeloid dendritic cells [163].

In addition to altered immune cell populations, disrupted immunoregulatory mechanisms are associated with infertility and pregnancy loss. Certain combinations of maternal killer immunoglobulin receptors (KIRs) and fetal HLA-C variants correlate with pregnancy loss [164], as does reduced HLA-G expression [18,165]. Studies in mice implicate the deposition of complement C3b on the placental vasculature early in gestation in conceptus demise [166], and, in humans, elevated placental complement activity is linked to pregnancy loss [167]. Alterations in expression of B7 costimulatory pathways and apoptosis-inducing tumor necrosis factor (TNF) superfamily members may also be disrupted in pregnancy losses [168,169].

Infection — Interruption of pregnancy by a variety of mechanisms is most common during the periimplantation period. Infection of the decidua, placenta, and fetal membranes appears to be one cause of early pregnancy loss and preterm birth [170-172]. Infection at the maternal-fetal interface may directly activate the trophoblast, decidual stroma, or chorioamniotic membranes to generate either a proinflammatory or proapoptotic response that in turn may lead to a disruption in the normal distribution, phenotype, and function of the decidual immune cells. Similarly, infection may impact the function of gestational tissues and cell types. The pathways leading from infection to preterm labor are not completely understood, although there is increasing evidence to suggest that innate immune receptors, such as Toll-like receptors and Nod-like receptors, may play a pivotal mechanistic role [4,173,174]. (See "Spontaneous preterm birth: Pathogenesis".)

Autoimmune disease and recurrent pregnancy loss — Females with autoimmune disease are at high risk for adverse pregnancy outcomes, such as recurrent pregnancy loss, as well as late gestational complications, such as preeclampsia. (See "Pregnancy in women with systemic lupus erythematosus" and "Thrombocytopenia in pregnancy" and "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment" and "Management of myasthenia gravis in pregnancy" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

In particular, females with antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) are at high risk for recurrent spontaneous miscarriage, preeclampsia, placental insufficiency, and intrauterine growth restriction (IUGR) [175]. In vivo animal studies have shown that aPL target the trophoblast and decidua and trigger elevated local and systemic TNF-alpha levels, elevated tissue factor expression and complement C3 deposition within the decidua, and a neutrophilic infiltration in the decidua [176-181]. Blocking TNF-alpha, the complement pathway, or tissue factor prevents aPL-mediated pregnancy failure and the associated inflammation [176,178,179], suggesting that pregnancy failure in APS patients is a result of inflammation rather than thrombosis at the maternal-fetal interface. An ongoing clinical trial is testing anti-TNF-alpha therapy, certolizumab (IMPACT; NCT03152058) in females with obstetric APS [182]. There is also a case report of the use of the complement inhibitor, eculizumab, in a pregnant patient with APS [183]. Studies using human first trimester trophoblast have demonstrated that aPL trigger an inflammatory response via the Toll-like receptor 4 (TLR4) and NLRP3 inflammasome signaling pathways. In addition, aPL inhibit the ability of the trophoblast to migrate and alter the cell's angiogenic factor production [184-187]. Thus, aPL may directly alter trophoblast function, induce placental inflammation, and alter the immune cell profile at the maternal-fetal interface through innate immune pathways.

Recurrent pregnancy loss and therapeutic approaches — Immunization of potential mothers with paternal or third-party leukocytes to improve reproductive success was, in the past, a popular method of putatively improving livebirth rates [188]. This strategy developed because homozygosity within couples, particularly at some HLA loci, is associated with modestly reduced fertility [189,190]. Thus, leukocyte immunization was thought to introduce a needed measure of immune recognition and stimulation. However, a multicenter study showed conclusively that leukocyte immunization was not effective and strongly suggested that reproductive outcomes might be worsened rather than improved by this intervention [191]. In addition, a randomized clinical trial of intravenous immune globulin treatment in females with repeated, unexplained in vitro fertilization failure found no improvement in the livebirth rate [192]. A meta-analysis further confirmed that there is insufficient evidence to support the use of these treatments for pregnancy losses [193]. (See "Recurrent pregnancy loss: Evaluation" and "Recurrent pregnancy loss: Management".)

Other therapeutic possibilities for recurrent pregnancy loss include anticoagulants (low-molecular-weight heparin, aspirin), hormones (progesterone), and immunomodulators (granulocyte macrophage-colony stimulating factor [GM-CSF], human growth hormone [hCG], macrophage-colony stimulating factor [M-CSF]) [194].

FETAL IMMUNE SYSTEM — Contributions of the fetal immune system to maternal-fetal immunologic interactions are not well understood. Some evidence suggests that the fetal immune system is unable to mount an anti-maternal immune response until mid- to late pregnancy. As an example, placental macrophages do not express human leukocyte antigen (HLA) class II antigens until the second trimester. Therefore, they are incapable of acting as fully effective antigen-presenting cells until this time [195]. In contrast, another study showed that fetal T cells were highly responsive to stimulation but were biased towards developing into regulatory T cells (Tregs), which are important in tolerance [196]. However, if fetal T cells are able to mount a response to maternal antigens, these fetal T cells may play a role in preterm labor [197].

Immunoglobulins — Immunoglobulin G (IgG) is transferred transplacentally from the mother to the fetus during the third trimester, although other classes of immunoglobulins are not under normal circumstances. Maternal IgG antibodies are usually beneficial to the infant, but certain maternal antibodies may result in disease in the newborn infant, such as hemolytic disease of the newborn (Rh incompatibility/Rh disease) [198]. Transplacental immunoglobulin transfer is reviewed separately. (See "Placental development and physiology", section on 'Immunoglobulin G transfer'.)

FUTURE DIRECTIONS — Although much is now known of the immunologic conditions that lead to successful pregnancy, much remains to be learned. Promising areas of research include the involvement of human leukocyte antigen (HLA) G in angiogenesis and autoimmune disorders and the effect of complement activation on dysregulation of angiogenesis leading to intrauterine fetal growth restriction [199-201]. Utilization of new genomics, proteomics, and immunophenotyping techniques may assist [112,202]. Immunomodulators and/or manipulation of innate immune processes may also provide new avenues for therapeutics [194,203].

SUMMARY

●Prevention of immune rejection of the fetus requires local immunologic adaptations within the mother, resulting in a state in which cytotoxic adaptive immune responses are diminished, bypassed, or even abrogated while regulatory adaptive immunity is enhanced. In contrast, innate (natural) immunity remains intact, serving two purposes: one, to continue to provide host defense against infection, and two, to interact with fetal tissues to promote successful placentation and pregnancy. (See 'Introduction' above.)

●Trophoblast cells protect the embryo itself and certain components of the extraembryonic membranes. Multiple strategies are used by these cells to avoid maternal immune cells and antibody-mediated cell destruction, including altered human leukocyte antigen (HLA) expression, synthesis of immunoregulatory molecules, and expression of high levels of complement regulatory proteins that protect the extraembryonic tissues from maternal anti-paternal cytotoxic antibodies. (See 'Immune defense mechanisms of the placenta and extraplacental membranes' above.)

●Uterine changes during pregnancy also help contribute to maternal immune adaptation, including alterations in the relative proportions, phenotype, and functions of leukocyte subpopulations, induction of immunoregulatory molecules (progesterone, prostaglandins), and changes in cytokine profiles across gestation. (See 'Local immune adaptation in the pregnant uterus' above.)

●Loss of potential pregnancies prior to or during implantation is common. Causes include genetic and endocrine abnormalities and autoantibodies, such as antiphospholipid antibodies (aPLs). Other potential causes are immune dysregulation and infection. Insults such as infection and aPLs can alter normal placental function and mechanisms of immune tolerance and can disrupt the normal trophoblast-maternal immune system crosstalk, resulting in other adverse pregnancy outcomes, such as preterm labor and preeclampsia. (See 'Immune factors in early pregnancy loss' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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  162. De Carolis C, Perricone C, Perricone R. NK cells, autoantibodies, and immunologic infertility: a complex interplay. Clin Rev Allergy Immunol 2010; 39:166.
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  165. Dahl M, Hviid TV. Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss. Hum Reprod Update 2012; 18:92.
  166. Triebwasser MP, Wu X, Bertram P, et al. Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse. Am J Reprod Immunol 2018; 80:e12997.
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  191. Ober C, Karrison T, Odem RR, et al. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet 1999; 354:365.
  192. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial. Fertil Steril 2000; 74:1108.
  193. Rasmark Roepke E, Hellgren M, Hjertberg R, et al. Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses. Acta Obstet Gynecol Scand 2018; 97:921.
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  200. Nicolae D, Cox NJ, Lester LA, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005; 76:349.
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Topic 3966 Version 24.0

References

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2 : Immune regulation of conception and embryo implantation-all about quality control?

3 : Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function.

4 : Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function.

5 : Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?

6 : Regulatory T cells and their role in pregnancy.

7 : The impact of dendritic cells on angiogenic responses at the fetal-maternal interface.

8 : Inflammation and implantation.

9 : The contribution of macrophages to normal and pathological pregnancies.

10 : Natural killer cell-triggered vascular transformation: maternal care before birth?

11 : The danger model: a renewed sense of self.

12 : Is the trophoblast an immune regulator? The role of Toll-like receptors during pregnancy.

13 : Immunology of the Placenta.

14 : Naturally acquired microchimerism.

15 : Naturally acquired microchimerism.

16 : Major histocompatibility complex (MHC)-mediated immune regulation of decidual leukocytes at the fetal-maternal interface.

17 : Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition.

18 : HLA-G: At the Interface of Maternal-Fetal Tolerance.

19 : HLA-G: At the Interface of Maternal-Fetal Tolerance.

20 : HLA-G: At the Interface of Maternal-Fetal Tolerance.

21 : The role of HLA-G in human pregnancy.

22 : Regulation of immune responses through inhibitory receptors.

23 : Interaction between HLA-G and monocyte/macrophages in human pregnancy.

24 : HLA-G Orchestrates the Early Interaction of Human Trophoblasts with the Maternal Niche.

25 : The role of decidual immune cells on human pregnancy.

26 : The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface.

27 : Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.

28 : Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction.

29 : NLRP2 is a suppressor of NF-ƙB signaling and HLA-C expression in human trophoblasts†,‡.

30 : Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8.

31 : Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways.

32 : Soluble HLA-G circulates in maternal blood during pregnancy.

33 : Synthesis of beta(2)-microglobulin-free, disulphide-linked HLA-G5 homodimers in human placental villous cytotrophoblast cells.

34 : HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4.

35 : Soluble human leukocyte antigen G5 polarizes differentiation of macrophages toward a decidual macrophage-like phenotype.

36 : Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells.

37 : Expression of class I HLA genes by trophoblast cells. Analysis by in situ hybridization.

38 : Identification of class I MHC mRNA in human first trimester trophoblast cells by in situ hybridization.

39 : Soluble HLA-G in human placentas: synthesis in trophoblasts and interferon-gamma-activated macrophages but not placental fibroblasts.

40 : Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression.

41 : B7 family molecules are favorably positioned at the human maternal-fetal interface.

42 : B7 family molecules as regulators of the maternal immune system in pregnancy.

43 : Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy.

44 : Prevention of allogeneic fetal rejection by tryptophan catabolism.

45 : Effect of Indoleamine 2,3-Dioxygenase Expressed in HTR-8/SVneo Cells on Decidual NK Cell Cytotoxicity.

46 : Tumor necrosis factors: pivotal components of pregnancy?

47 : Expression of Fas ligand by human cytotrophoblasts: implications in placentation and fetal survival.

48 : TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege.

49 : Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines.

50 : Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas.

51 : First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis.

52 : Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level.

53 : Immunomodulatory molecules are released from the first trimester and term placenta via exosomes.

54 : The role of placental exosomes in reproduction.

55 : Circulating microparticles in normal pregnancy and pre-eclampsia.

56 : Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1.

57 : Unique microRNA Signals in Plasma Exosomes from Pregnancies Complicated by Preeclampsia.

58 : Human placental trophoblasts confer viral resistance to recipient cells.

59 : Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging.

60 : Cytokine secretion by human fetal membranes, decidua and placenta at term.

61 : Cytokine secretion by human fetal membranes, decidua and placenta at term.

62 : IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.

63 : A deficiency of placental IL-10 in preeclampsia.

64 : Interleukin-10: a multi-faceted agent of pregnancy.

65 : Thymic stromal lymphopoietin from trophoblasts induces dendritic cell-mediated regulatory TH2 bias in the decidua during early gestation in humans.

66 : Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells.

67 : Complement regulatory proteins at the feto-maternal interface during human placental development: distribution of CD59 by comparison with membrane cofactor protein (CD46) and decay accelerating factor (CD55).

68 : A critical role for murine complement regulator crry in fetomaternal tolerance.

69 : Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.

70 : Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function.

71 : Dendritic cells in the human decidua.

72 : Immunocytochemical characterization of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle.

73 : Elsevier Trophoblast Research Award Lecture: Unique properties of decidual T cells and their role in immune regulation during human pregnancy.

74 : The Role of Decidual Macrophages During Normal and Pathological Pregnancy.

75 : Modulators of the Balance between M1 and M2 Macrophages during Pregnancy.

76 : Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface.

77 : Three macrophage subsets are identified in the uterus during early human pregnancy.

78 : Macrophages and apoptotic cell clearance during pregnancy.

79 : Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy.

80 : Review: Trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel.

81 : The role of macrophages in utero-placental interactions during normal and pathological pregnancy.

82 : The origins and end-organ consequence of pre-eclampsia.

83 : Placental Hofbauer cells and complications of pregnancy.

84 : Decreased levels of folate receptor-βand reduced numbers of fetal macrophages (Hofbauer cells) in placentas from pregnancies with severe pre-eclampsia.

85 : Toll-like receptor-mediated responses by placental Hofbauer cells (HBCs): a potential pro-inflammatory role for fetal M2 macrophages.

86 : To serve and to protect: the role of decidual innate immune cells on human pregnancy.

87 : Human decidual NK cells form immature activating synapses and are not cytotoxic.

88 : Uterine natural killer cells: insights into lineage relationships and functions from studies of pregnancies in mutant and transgenic mice

89 : Synthesis and granular localization of tumor necrosis factor-alpha in activated NK cells in the pregnant mouse uterus.

90 : The role of perforin-expression by granular metrial gland cells in pregnancy.

91 : Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis.

92 : Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies.

93 : Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium.

94 : Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage.

95 : Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage.

96 : How Does the maternal immune system contribute to the development of pre-eclampsia?

97 : Immunological modes of pregnancy loss: inflammation, immune effectors, and stress.

98 : Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy.

99 : Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss.

100 : Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.

101 : Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice.

102 : Identification of diverse innate lymphoid cells in human decidua.

103 : Group 3 innate lymphoid cells regulate neutrophil migration and function in human decidua.

104 : Innate lymphoid cells at the human maternal-fetal interface in spontaneous preterm labor.

105 : In vivo dendritic cell depletion reduces breeding efficiency, affecting implantation and early placental development in mice.

106 : Uterine DCs are crucial for decidua formation during embryo implantation in mice.

107 : An immunological insight into the origins of pre-eclampsia.

108 : Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice.

109 : Dendritic cell function at the maternal-fetal interface.

110 : Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua.

111 : Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia.

112 : Computational flow cytometry analysis reveals a unique immune signature of the human maternal-fetal interface.

113 : Characterization of gamma delta T lymphocytes at the maternal-fetal interface.

114 : Involvement of decidual Valpha14 NKT cells in abortion.

115 : Pregnancy and gamma/delta T cells: taking on the hard questions.

116 : The role ofγδ-T cells during human pregnancy.

117 : CD8+ effector T cells at the fetal-maternal interface, balancing fetal tolerance and antiviral immunity.

118 : Adaptive immune responses during pregnancy.

119 : Maternal effector T cells within decidua: The adaptive immune response to pregnancy?

120 : FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua.

121 : Regulatory T cells: regulators of life.

122 : Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes.

123 : Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.

124 : Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance.

125 : Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia.

126 : Inducing tolerance to pregnancy.

127 : Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy.

128 : Mast cell-mediated and associated disorders in pregnancy: a risky game with an uncertain outcome?

129 : Immune cells in term and preterm labor.

130 : B cells: the old new players in reproductive immunology.

131 : The role of pregnancy-associated hormones in the development and function of regulatory B cells.

132 : IFN type I and II induce BAFF secretion from human decidual stromal cells.

133 : Isolation of Leukocytes from the Human Maternal-fetal Interface.

134 : Progesterone in pregnancy; receptor-ligand interaction and signaling pathways.

135 : A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance.

136 : Regulation of TNF-alpha production in activated mouse macrophages by progesterone.

137 : Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?

138 : Synthesis of T helper 2-type cytokines at the maternal-fetal interface.

139 : Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review.

140 : Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition.

141 : Tumor necrosis factor in preterm and term labor.

142 : Tumor necrosis factor in preterm and term labor.

143 : Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.

144 : Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation.

145 : Monocytes are progressively activated in the circulation of pregnant women.

146 : Pregnancy, but not the allergic status, influences spontaneous and induced interleukin-1beta (IL-1beta), IL-6, IL-10 and IL-12 responses.

147 : Longitudinal modulation of immune system cytokine profile during pregnancy.

148 : Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle.

149 : Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells.

150 : T cell awareness of paternal alloantigens during pregnancy.

151 : Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.

152 : Regulatory T cells mediate maternal tolerance to the fetus.

153 : Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.

154 : Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy.

155 : IL-10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau.

156 : The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice.

157 : Cutting edge: IL-10-producing regulatory B cells in early human pregnancy.

158 : A national survey on public perceptions of miscarriage.

159 : Defective implantation and placentation: laying the blueprint for pregnancy complications.

160 : Influence of semen on inflammatory modulators of embryo implantation.

161 : Natural killer cells, miscarriage, and infertility.

162 : NK cells, autoantibodies, and immunologic infertility: a complex interplay.

163 : Association of peripheral blood dendritic cells with recurrent pregnancy loss: a case-controlled study.

164 : Immune etiology of recurrent pregnancy loss and its diagnosis.

165 : Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss.

166 : Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse.

167 : The complement system and adverse pregnancy outcomes.

168 : The costimulatory signal upregulation is associated with Th1 bias at the maternal-fetal interface in human miscarriage.

169 : FAS and FAS-L genotype and expression in patients with recurrent pregnancy loss.

170 : The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity--a review.

171 : A review of premature birth and subclinical infection.

172 : Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor.

173 : Pattern recognition at the maternal-fetal interface.

174 : The role of the Nod-like receptor family in trophoblast innate immune responses.

175 : Autoimmunity and recurrent pregnancy losses.

176 : Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.

177 : Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation.

178 : TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss.

179 : Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury.

180 : Complement activation and pregnancy failure.

181 : Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome.

182 : 16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends.

183 : Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome: A case report.

184 : Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway.

185 : Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity.

186 : Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin.

187 : A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1βproduction by human first trimester trophoblast.

188 : Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells.

189 : Inbreeding effects on fertility in humans: evidence for reproductive compensation.

190 : Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

191 : Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial.

192 : Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial.

193 : Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses.

194 : Multiple pregnancy failures: an immunological paradigm.

195 : Uterine macrophages and environmental programming for pregnancy success.

196 : Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

197 : Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γand TNF-α.

198 : Newborn illnesses caused by transplacental antibodies.

199 : Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells.

200 : Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21.

201 : Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction.

202 : Proteomics, part II: the emerging role of proteomics over genomics in spontaneous preterm labor/birth.

203 : Antagonizing toll-like receptors to prevent preterm labor.

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