Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

The maternal–fetal interface is an immunologically unique site that allows the tolerance to the allogenic fetus and maintains host defense against possible pathogens. Balanced immune responses are required for the maintenance of successful pregnancy. It has been demonstrated that innate immune disturbances may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE); hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome; intrauterine growth restriction (IUGR); and recurrent spontaneous abortion (RSA). Observational studies suggest that immunomodulatory treatments in pregnancy‐specific complications may improve both the hematological/biochemical features in the mother and the perinatal outcomes. The following review will discuss how recent and relevant findings in the field of the innate immunity have advanced our understanding of the role of inflammation and innate immune system in the pathogenesis of pregnancy failure and will discuss the therapeutic outcomes of the existing studies and clinical trials in light of these new insights.     

Natural mechanisms for evading graft rejection: the fetus as an allograft

Most primitive multicellular animals mount allogeneic immune responses to protect themselves from invasion by foreign organisms. The reproductive success of eutherian mammals, in which the maternal immune system is in direct contact with the semi-allogeneic fetus, depends on the ability to control allogeneic immune responses. Multiple, overlapping mechanisms exist to prevent maternal allogeneic immune responses towards the fetus while maintaining the capacity to mount a defense against infectious organisms. The formation of an anatomical barrier between mother and fetus, lack of maternal immune responsiveness, and a lack of expression of allogeneic molecules by the fetus have been proposed as mechanisms to account for the lack of fetal rejection during pregnancy. These mechanisms have helped us begin to understand how rejection of the fetus is avoided; however, these mechanisms do not completely explain how the fetus evades the maternal immune system. Site-specific suppression, in which maternal immune responses are controlled locally at the maternal- fetal interface, plays a fundamental role in controlling maternal allogeneic immune responses. Stem cells, both adult and embryonic, might use mechanisms similar to those of the fetus to avoid rejection. Future discoveries in the field of reproductive immunology will help us understand not only immune regulation during pregnancy, but also how immune responses towards organ and cellular transplants might be controlled.

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Immunoregulation of fetal and anti-paternal immune responses

Immunological tolerance to the fetus is essential for fetal survival during pregnancy. The semi-allogeneic fetus expresses genes foreign to the mother that can be recognized by maternal T cells. Under times of stress or infection, deleterious immune responses can result in fetal destruction and/or maternal death. Exposure to non-maternal antigens begins as early as insemination and some of the mechanisms required to prevent maternal priming against these antigens are in place before sexual encounter. Continuous and overlapping regulatory mechanisms must cooperate to allow the best chances for fertilization, implantation, and healthy gestation, simultaneously protecting the fetus from maternal immune attack yet making minimal compromises in resistance to infection. Several types of immune cell from both the innate and adaptive arms of the immune system help protect both the mother and fetus during pregnancy. It’s the intricate communication and interplay between the immune system and the endocrine system that will ultimately decide the success or fate of the developing fetus.     

Future directions of clinical laboratory evaluation ol pregnancy

In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss （RPL） or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing： one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer （NK） cells （combinations of killer cell immunoglobulin-like receptor （KIR） family genes with HLA-C haplotypes） that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors.     

胎盘在妊娠免疫耐受作用中的研究进展

胎儿携带二分之一父方基因和二分之一母方基因在母体宫内,可视为移入母体内的半异体移植物,但成功妊娠的胎儿却不被母体排斥,这是由于妊娠期的母体存在免疫耐受。其中胎盘的滋养层和底蜕膜上有许多免疫因子可使胎儿得以逃避母体的免疫攻击：胎盘自身的机械性屏障作用也起重要作用；HLA-G，E可抑制妊娠时T细胞及NK细胞的表达；补体调节蛋白可通过干扰膜攻击复合物的形成而利于母胎免疫；母体Treg细胞在正常妊娠时的表达量高于非妊娠时的表达量，也参与了母胎免疫耐受。     

The Role of Macrophages in Promoting and Maintaining Homeostasis at the Fetal–Maternal Interface

A successful pregnancy requires that the maternal immune system adapts properly to avoid rejection of the semi‐allogeneic fetus without compromising the ability to protect the mother and the fetus against infections. In this review, we describe the role of decidual macrophages in creating a homeostatic environment at the fetal–maternal interface. We also discuss their role in pregnancy complications as well as future possibilities to modulate macrophage function therapeutically. Decidual macrophages are enriched at the fetal–maternal interface and play a major role in the regulation of inflammatory responses and the maintenance of a tolerant environment. Their function is, however, not restricted to immune tolerance, but extends to include functions such as the recognition and clearance of infections, the clearance of apoptotic debris, and tissue remodeling. Decidual macrophages seem to largely function as tissue‐resident macrophages that are crucial for maintaining homeostasis and reproductive success.     

A new era in reproductive medicine: consequences of third-party oocyte donation for maternal and fetal health

The fetus is a semi-allograft for the maternal host in natural pregnancy, but the fetus is a complete allograft after oocyte donation (OD), and there is greater antigenic dissimilarity with the mother. Thus, OD pregnancy is a good model for understanding how the fetus is protected by the maternal immune system. Recent clinical data have revealed a higher risk of miscarriage, gestational hypertension, preterm birth, and low birth weight with OD pregnancy. There is also a higher incidence of chorionic deciduitis, dense fibrinoid deposits in the chorionic basal plate, inflammatory lesions in the chorionic plate, and C4d deposition on syncytiotrophoblasts in OD pregnancy. Impaired accumulation of T cells, regulatory T (Treg) cells, natural killer (NK) cells, and monocytes in the decidua basalis and poor remodeling of spiral arteries are observed in OD pregnancy irrespective of whether preeclampsia occurs. These findings may partly explain why OD pregnancy is associated with a high risk of gestational hypertension and preeclampsia. We need to clarify the immunological and pathological differences between uncomplicated and complicated OD pregnancy. In uncomplicated OD pregnancy, the level of HLA match between mother and baby is significantly higher than would be expected by chance, suggesting that miscarriage may be frequent with marked HLA mismatch. This review discusses the relationship between various aspects of the immune system and complications of OD pregnancy.     

HLA-G--母胎界面的一个免疫耐受分子

正常妊娠显示母体对同种异体胎儿的一种免疫耐受,HLA-G蛋白作为HLA移植抗原的代表限制性表达在母胎界面上,不仅不引起母体对胎儿的免疫排斥反应,相反被认为在母胎免疫耐受中起积极作用.     

The immunology of successful pregnancy

Immune responses play an important role in various reproductive processes, including ovulation, menstruation and parturition. Clearly, during pregnancy, when the mother must accept a semi-allogeneic fetus, immune responses also play a very important role. This was first recognized by Medawar in 1953, when the concept of the fetal allograft was presented in order to explain the immunological relationship between mother and fetus. Since then, the immunology of pregnancy has been the leading subject within reproductive immunology research. Yet, the question of why the semi-allogeneic fetus is not rejected by the mother remains unresolved. The present review provides an update of current knowledge on the subject of the so-called 'immunological paradox of pregnancy'.     

Interaction of pregnancy and autoimmune rheumatic disease

During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.     

Imitating a stress response: A new hypothesis about the innate immune system’s role in pregnancy

Recent research challenges long-held hypotheses about mechanisms through which pregnancy induces maternal immune suppression or tolerance of the embryo/fetus. It is now understood that normal pregnancy engages the immune system and that the immune milieu changes with advancing gestation. We suggest that pregnancy mimics the innate immune system’s response to stress, causing a sterile inflammatory response that is necessary for successful reproduction. The relationship between external stressors and immunomodulation in pregnancy has been acknowledged, but the specific mechanisms are still being explicated.Implantation and the first trimester are times of immune activation and intensive inflammation in the uterine environment. A period of immune quiescence during the second trimester allows for the growth and development of the maturing fetus. Labor is also an inflammatory event. The length of gestation and timing of parturition can be influenced by environmental stressors. These stressors affect pregnancy through neuroendocrine interaction with the immune system, specifically through the hypothalamic–pituitary–adrenal (HPA) axis and the hypothalamic–pituitary–ovarian axis. Trophoblastic cells that constitute the maternal–fetal interface appear to harness the maternal immune system to promote and maximize the reproductive success of the mother and fetus. Pregnancy is a time of upregulated innate immune responses and decreased adaptive, cell-mediated responses. The inflammatory processes of pregnancy resemble an immune response to brief naturalistic stressors: there is a shift from T helper (Th) 1 to T helper (Th) 2 dominant adaptive immunity with a concomitant shift in cytokine production, decreased proliferation of T cells, and decreased cytotoxicity of natural killer (NK) cells.Inclusion of both murine and human studies, allows an exploration of insights into how trophoblasts influence the activity of the maternal innate immune system during gestation.     

Immunomodulation of the mother during pregnancy

The concept that the immune responsiveness of the mother is reduced during pregnancy arose from studies which appeared to show that immune response to certain antigens is reduced during pregnancy (1, 2). Various substances claimed to have immunosuppressive or immunomodulating effect include alpha fetoprotein, placental proteins, early pregnancy factor (EPF), human chorionic gonadotropin (HCG), corticosteroids, estrogens, androgens and progesterone (2). To summarise a body of literature, there is very little change in the immune competence of the mother during pregnancy. This makes sense, as generalized immunosuppression would be a risky way to ensure the survival of the fetus. Immune enhancement and subsequent immunomodulation of the mother is likely to be the mechanism operative during pregnancy. It is conceivable that the overall immune response in pregnancy could be the net result of an interplay of various interactions that may be operating to ensure non-rejection of the antigenically alien fetus while at the same time preventing a state of excessive immunosuppression. Such a dynamic homeostatic mechanism appears to be important for the successful completion of pregnancy.     

Immune responses in the human female reproductive tract

Mucosal surfaces are key interfaces between the host and its environment, but also constitute ports of entry for numerous pathogens. The gut and lung mucosae act as points of nutrient and gas exchange, respectively, but the physiological purpose of the female reproductive tract (FRT) is to allow implantation and development of the fetus. Our understanding of immune responses in the FRT has traditionally lagged behind our grasp of the situation at other mucosal sites, but recently reproductive immunologists have begun to make rapid progress in this challenging area. Here, we review current knowledge of immune responses in the human FRT and their heterogeneity within and between compartments. In the commensal-rich vagina, the immune system must allow the growth of beneficial microbes, whereas the key challenge in the uterus is allowing the growth of the semi-allogeneic fetus. In both compartments, these objectives must be balanced with the need to eliminate pathogens. Our developing understanding of immune responses in the FRT will help us develop interventions to prevent the spread of sexually transmitted diseases and to improve outcomes of pregnancy for mothers and babies.     

Role of dendritic cells in the regulation of maternal immune responses to the fetus during mammalian gestation

Successful mammalian pregnancy relies on the action of sophisticated regulatory mechanisms that allow the fetus (a semi-allograft) to grow and develop in the uterus in spite of being recognized by maternal immune cells. Among several immunocompetent cells present at the maternal fetal interface, dendritic cells (DC) seem to be of particular relevance for pregnancy maintenance given their unique ability to induce both antigen-specific immunity and tolerance. Thus, these cells would be potentially suitable candidates for the regulation of local immune responses within the uterus necessary to meet the difficult task of protecting the mother from infection without compromising fetal survival. Current evidence on decidual DC phenotype and function, and their role in the regulation of the maternal immune system during mouse and human pregnancy are discussed and reviewed herein; highlighting novel DC functions that seem to be of great importance for a successful pregnancy outcome.     

Immunology of pregnancy

Pregnancy is a unique event in which a genetically and immunologically foreign fetus usually survives to full term without apparent rejection by the mother's immune system. Over the past decade, more information has been gathered to provide insight into the complex immunological mechanisms that allow the fetus to grow and survive in most cases. Whereas the maternal-fetal interface was once felt to be an immunologically privileged site with complete separation between the fetus and the mother, it is now known that recognition of the foreign fetus does occur. However, despite this immunological recognition, several mechanisms have been discovered which may explain why the mother does not reject the foreign fetus. These mechanisms include fetal factors such as trophoblast cell properties and altered MHC Class I expression as well as local maternal factors such as specialized uterine natural killer cells and a shifting of the T-helper cell cytokine profile from a type 1 to a type II array. Other novel immunomodulators are found to be expressed in the local uterine environment to aid in fetal survival. Furthermore, the persistence of fetal cells in the maternal circulation long after pregnancy is over (termed chronic microchimerism) and may have implications for autoimmune diseases. This review presents investigations and developments relevant to an understanding as to why the fetus is not rejected by the maternal immune system.     

Alternative pathway activation in pregnancy,a measured amount “complements” a successful pregnancy,too much results in adverse events

During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk to the mother. One of the most prominent adaptations involves the immune system. The semi-allogenic fetoplacental unit has non-self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non-self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi-allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy-specific disorders, are discussed.     

The complement system in the pathophysiology of pregnancy

A fully active complement system deriving from the maternal circulation as well as from local production by various cell source is present in the placenta. The role of this system at the placental level, as in any other tissue in the body, is to protect both the fetus and the mother against infectious and other toxic agents. As fetal tissues are semi-allogeneic and alloantibodies commonly develop in the mother, the placenta is potentially subject to complement-mediated immune attack at the feto-maternal interface with the potential risk of fetal loss. Uncontrolled complement activation is prevented in successful pregnancy by the three regulatory proteins DAF, MCP and CD59 positioned on the surface of trophoblasts. The critical role played by these complement regulators is supported by the embryonic lethality observed in mice deficient in the complement regulator Crry. Excessive complement activation in the placenta places the fetus at risk for growth restriction or death. The role played by the complement system in the fetal damage induced by anti-phospholipid antibodies in a mouse model will be examined.     

Immunology of hepatic diseases during pregnancy

The mother’s immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.     

Asthma in the pregnant patient: a review

The occurrence of asthma during pregnancy is not an uncommon event and dictates specific treatment consideration. Proper management requires an understanding of the normal physiologic respiratory alterations during pregnancy, factors affecting maternal-fetal gas exchange, and use of drug therapy considered safe for both the mother and fetus. With optimum modern day therapy, a favorable outcome for both mother and fetus can be expected.