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 . 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 .
Trophoblast cells — Trophoblast cells are the specific placental 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 . This may be explained, in part, by the presence of gaps in the syncytiotrophoblast, particularly later in gestation .
These subpopulations of trophoblasts (extravillous cytotrophoblast cells, chorion membrane cytotrophoblasts, and endovascular trophoblasts) are variably exposed to maternal hematopoietic elements in the decidua, the fetal membranes, 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 fetal 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 .
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 . 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 .
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, HLA-F, and HLA-G may activate pathways in dNK cells, macrophages, and T cells that promote trophoblast migration and placentation [18,24,25].
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 . These acquired HLA-G+ NK and T cells are immunosuppressive . The HLA class Ia antigen, HLA-C, is expressed on extravillous trophoblast and may have important interactions with leukocytes in some mothers [1,27]. As an example, certain combinations of maternal KIRs and fetal HLA-C variants correlate with low birth weight and preeclampsia [28,29]. HLA-C expression may be regulated by Nod-like receptor family pyrin domain-containing 2 (NLRP2) .
HLA-G messenger ribonucleic acid (mRNA) can be alternatively spliced to yield membrane-bound and soluble variants. Soluble HLA-G is associated with immunomodulatory functions and promotion of placentation [18,31]. Antigen-presenting cells expressing either a soluble or membrane-bound form of HLA-G repress T cell alloproliferation via this pathway . 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 [33-37].
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 . 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 [1,18,34,39,40].
●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 .
●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) [42-44]. Another B7 family member, B7H3 has been reported to regulate trophoblast invasion through RhoA/Rho-dependent coiled-coil kinase (ROCK) 2 signaling and reduces dNK cell secretion of interleukin (IL) 8 and IFN-inducible protein (IP) 10 .
●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 . Evidence is beginning to emerge in support of this potential mechanism in humans . One study reported that IDO+ decidual macrophages supported trophoblast survival .
●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 [49-52]. 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 .
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 [54,55]. Some B7 family members, as well as HLA-G and HLA-E, can also be released from the placenta via exosomes and microvesicles [56,57]. 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 [58-61]. Exosome-mediated transfer of placental-specific microRNAs regulates trophoblast and maternal cell immunity to viral infections . A novel mechanism by which maternal immune cells can signal to the placental unit via exosomes has been proposed .
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 IL-10 and IL-4 [1,19,20,64,65]. 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 , and dysfunction of this pathway may be important in preeclampsia . Studies using IL-10-/- knockout mice have highlighted the potentially important protective role for this cytokine in pregnancy . 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) . 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]) [70,71]. 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 .
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 . 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 . 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 [74-76]. In addition, the uterine T cell population during pregnancy expands across gestation and is mostly regulatory in nature .
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 [78,79]. The placenta may promote this via secreted factors . At parturition, there is an accumulation of M1 decidual macrophages [78,79]. There are also subsets outside of conventional phenotyping [78,81]. 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 [9,80,82-84]. Aberrant macrophage numbers and activation may play a role in pregnancy complications, such as preeclampsia, intrauterine growth restriction (IUGR), or preterm birth [9,85,86]. 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 [87-89].
Similarly, the major roles of dNK cells may also be unique to pregnancy . Although dNK cells express a high level of cytotoxic factors, they are unable to form cytotoxic synapses to deliver granule contents to trophoblast cells  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 [92-95]. However, dNK cells are able to kill virally infected trophoblast cells, indicating a mechanism to protect the fetus . 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 . One study proposed that uNK cells maintain endometrial homeostasis by clearing senescent decidual cells . 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 [28,29,99-103]. 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 . 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 [104,105]. NK cell depletion compromises pregnancy in mice, further underscoring their importance during pregnancy .
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 [107,108]. At term, both ILC2s and ILC3s have been found in the decidua, and levels may increase in preterm birth .
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 [6,110,111]. However, alternative views exist. One is that dendritic cells may promote systemic immune tolerance during pregnancy . Another is that dendritic cells are trapped in the decidua to prevent the exposure of peripheral T cells to fetal antigens . 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 . Depletion of uterine dendritic cells in mice results in a severe impairment of implantation and embryo resorptions, highlighting their importance . Preeclampsia is also associated with persistence of decidual basalis macrophages and recruitment of dendritic cells [115,116]. 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 .
Gamma-delta T cells and a population of double-negative T lymphocytes (CD4-/CD8-) have been reported in pregnant uteri [118,119]. 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 [120,121]. Increased numbers of gamma-delta T cells may be associated with pregnancy loss . 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 [122-124].
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 [5,125,126]. 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 . These fetal-specific Tregs persist after delivery and rapidly reaccumulate during subsequent pregnancies, indicating a memory response . In a mouse model, increased numbers of Tregs are seen in response to an antigenic fetus . 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 [126,130,131].
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 [126,132].
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  and are higher in human pregnancies compared with nonpregnant females . In the mouse, they have been shown to promote an antiinflammatory state and contribute to tissue remodeling, angiogenesis, and spiral artery transformation .
In mice, glycan-mediated B cell suppression in pregnancy may prevent B cell responses to placental antigens . At the same time, 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 [136,137]. While the presence of CD19+ B cells in the human decidua throughout pregnancy has been reported [138,139], 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 . 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 [141,142].
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 [143,144] 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 . Similarly high levels of proinflammatory IL-1-beta and TNF-alpha in the amniotic fluids are associated with preterm birth [146,147]. 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 [4,125,148]. 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 . 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 .
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) [151-155], 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 [58-60].
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 . (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 [157-160]. 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 [161,162]. 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 .
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 . While approximately 60 percent of miscarriages can be accounted for by chromosomally abnormal embryos, the remainder are idiopathic  and, in many cases, are thought to arise from implantation failure . 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 "Female infertility: Causes".)
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 . 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 . Consequently, there have been efforts targeting NK cells in an attempt to cure infertility and miscarriage; however, well-controlled trials are lacking [167,168]. 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 , as are elevated levels of peripheral blood myeloid dendritic cells  and reduced indoleamine 2,3-dioxygenase-positive (IDO+) decidual macrophages .
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 , as does reduced HLA-G and HLA-E expression [18,57,171]. Studies in mice implicate the deposition of complement C3b on the placental vasculature early in gestation in conceptus demise , and, in humans, elevated placental complement activity is linked to pregnancy loss . Alterations in expression of B7 costimulatory pathways and apoptosis-inducing tumor necrosis factor (TNF) superfamily members may also be disrupted in pregnancy losses [45,174,175].
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 [176-178]. 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 [4,179,180]. (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) . 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 [182-187]. Blocking TNF-alpha, the complement pathway, or tissue factor prevents aPL-mediated pregnancy failure and the associated inflammation [182,184,185], 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 . There is also a case report of the use of the complement inhibitor, eculizumab, in a pregnant patient with APS . 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 [190-193]. 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 . This strategy developed because homozygosity within couples, particularly at some HLA loci, is associated with modestly reduced fertility [195,196]. 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 . 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 . A meta-analysis further confirmed that there is insufficient evidence to support the use of these treatments for pregnancy losses . (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]) .
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 . 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 . 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 .
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) . 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 [205-207]. Utilization of new genomics, proteomics, and immunophenotyping techniques may assist [117,208]. Immunomodulators and/or manipulation of innate immune processes may also provide new avenues for therapeutics [200,209].
●Overview – 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.)
●Role of trophoblast cells – 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 immune adaptations – 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.)
●Immune factors in early pregnancy loss – 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 earlier versions of this topic review.
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