Immunology of Pregnancy 2013

In this introduction, we briefly review the “evolution of viviparity” as would say Peter Medawar, encompassing not only the vertebrates but the (very early) invertebrates, in order to see the cohabitation with the adaptive and innate immune system in an evolutionary perspective. We personally believe this approach is of importance, since viviparity and the “allograft problem” did not emerge AFTER the adaptive immune system, but LONG before, as seen for example with … placental velvet worms. Even if the placentae in such species are obviously not as complex as mammalian ones, they are “non self allografts”. Thus, they, and other aspects, lead to heretic questions which might lead to reconsider the approach of the foeto maternal relationship, too often seen as a confrontation rather than a symbiosis/cohabitation.

The vaginal innate immune system represents the first line of defense against foreign organisms and pathogenic microbes. Through its major components, a natural balance is maintained and disease is averted. Many recent advances have furthered our knowledge of this intricate equilibrium and the contribution of each element to the final homeostasis. Various adverse obstetric and gynecologic conditions have been traced to abnormalities in the vaginal environment. This review highlights the importance of this subject in future interventions and opens the venue for future research.

Immunological tolerance to developmental sperm antigens is not induced in males, because spermatogenesis begins first in the testis on puberty, much after the establishment of tolerance to self-antigens. If the blood-testes barrier, which isolates germ cells from the contact with local immune system, is impaired by some reasons, autoimmunity to sperm antigens could be induced and results in the development of autoimmune orchitis. Similarly, since spermatozoa are not self and isoantigens to females, if they are exposed repeatedly to sperm antigens by coitus, it is not surprising that isoimmunity to sperm antigens could be induced and develop antisperm antibodies (ASA) in females.

Following the introduction, studies on Immuno-pathogenesis of experimental autoimmune orchitis and ASA production in mammals will be reviewed. Autoimmune orchitis can be induced by active immunization with testicular antigens in a variety of animal species. Neonatal thymectomy and vasectomy also cause the development of orchitis. ASA can be detected by using various assay methods in men and women. However, not all the antibodies cause infertility. It is important to differentiate ASA that cause infertility, from those that do not. The relationship of ASA to male and female infertility, the mechanisms for infertility caused by ASA and the treatment of infertile patients with ASA are discussed.

Finally, our establishment and characterization of human monoclonal antibody derived from an infertile woman with ASA and biological and immunological functions of the target antigen are presented.

Prophylactic vaccines are being used for prevention of various infectious diseases. Development of vaccines for contraception is an interesting proposition to control increasing human population. Various hormones such as gonadotropin releasing hormone, follicle stimulating hormone, and human chorionic gonadotropin have been proposed as targets for immuno-contraception. In addition, gamete (spermatozoa, egg) specific proteins have also been proposed as candidate immunogens for developing contraceptive vaccines. Studies carried out in various animal species including humans, using a variety of target proteins, have established as proof of principle that vaccines can be developed for fertility inhibition. Current limitations for their use as human contraceptive vaccines pertain to failure to generate protective antibody response in hundred percent recipients and variability in the duration of protective antibody titres from individual to individual. In spite of these logistic hurdles, contraceptive vaccines based on gonadotropin releasing hormone and zona pellucida glycoproteins have excellent prospects for the management of wildlife population. To achieve this, there is need to develop novel vaccine delivery platforms for providing long lasting immunity.

Every ninth couple in Europe and USA is affected by implantation disorders and pregnancy wastage and majority of pregnancy losses occur before or during implantation. Therefore, understanding the cross talk between fetal and maternal components before, during and after their confrontations remains a major challenge. Human implantation may be described as a three steps process starting with the apposition and adhesion of a competent blastocyst to the endometrium epithelium and continuing by an extensive invasion throughout the first trimester of pregnancy in a receptive endometrium. The complex very highly reciprocal orchestrated process of human implantation leads to the essential construction of a haemochorial placenta. This chapter will detail the Human particularities of the implantation beginning by a maternal and paternal local preparation, a switch of the local immunity to establish transiently a local environment of immune tolerance. We will detail the role of hormone, cytokines, growth factors as well metalloproteases and transcription factors within this complex and evolutive dialogue.

Fetal-derived trophoblast cells are in contact with maternal immune cells in the human placenta, constituting the maternal-fetal interfaces. In contrast to most somatic cells, the different trophoblast subpopulations are devoid of polymorphic HLA-A and HLA-B expression whereas extravillous cytotrophoblast that invade the decidua basalis and spiral arteries in early pregnancy express HLA-C as well as the non polymorphic HLA-E, HLA-F and HLA-G. This unique pattern of HLA class I expression results in crucial functional consequences. Corresponding specific receptors for HLA-C (killer immunoglobulin-like receptors, KIR), HLA-E (CD94/NKG2A and CD94/NKG2C) and HLA-G (CD8, LILRB1, LILRB2, KIR2DL4, CD160) are present at different levels in decidual NK cells, macrophages and/or several other immune or non-immune cells. Maternal activating KIRs present on decidual NK cells exert a protector effect against human reproductive failure mediated by fetal HLA-C2. HLA-E, by interacting with CD94/NKG2C activating and/or CD94/NKG2A inhibitory receptors present on decidual NK cells contributes to modulate the combined signals mediated from multiple other activating and inhibitory receptors present at their cell surface. HLA-G unique structural features explain why HLA-G acts differently to other HLA class I molecules. Controversies on the expression of the different forms of HLA-G in the trophoblast are presented. Membrane and soluble HLA-G expressed by trophoblast interact locally with a number of receptors present on various maternal decidual cells. Such specific ligations modulate local cytokine, chemokine and angiogenic factor secretion that are likely to contribute to the good outcome of placental development and pregnancy. HLA-F binds to LILRB1 and LILRB2 receptors. HLA-F-2-microglobulin complex physically interacts in trans with MHC Class I heavy chains in an open conformer form, suggesting a possible role as chaperone to stabilize MHC Class I expression in the absence of peptides

Pregnancy has been described as an immunological paradox because the maternal immune system accepts the fetus even though it expresses paternal antigens. Since placental tissues express maternal and paternal genes the immune system of the mother must tolerate the fetus to avoid its rejection. Placental expression of MHC-I proteins appears to play an important role in the regulation of the maternal immune system and protection of the conceptus from immune-mediated rejection. There are two types of MHC-I proteins. Classical MHC-I proteins, also called MHC-Ia, are highly polymorphic and are expressed by most nucleated cells. The non-classical proteins, also called MHC-Ib, are less polymorphic, are expressed by limited types of cells and are known to have immune modulatory effects in some species. In order to protect the fetus from maternal immune recognition most species down-regulate the expression of placental MHC-Ia proteins. Another commonly used mechanism is the upregulation of MHC-Ib expression by the trophoblast cells. The role of MHC-I proteins in the placenta has been studied in several animal species. This chapter will summarize the current literature on the expression of MHC-I proteins by the placenta of domestic and laboratory species. A lot remains to be learned about the types, function and regulation of expression of placental MHC-I proteins in domestic and laboratory animals.

Controlled invasion of the trophoblast cells during early stages of embryonic development is one of the essential attributes leading to successful implantation. This involves two very crucial events i.e. initial attachment of the trophoblast cells to the maternal endometrium and later epithelial to mesenchymal transition of trophoblast cells leading to their dissociation from the cell column. These set of events are brought about by an orchestrated change in the expression of several adhesion molecules and the polar proteolytic degradation of the extra cellular matrix (ECM). A change in the expression of adhesion molecules like integrins, cadherins etc. helps in establishing close cell to cell association during the early phase of trophoblast attachment to the endometrial cells. Later, switch in their expression pattern enhances their interaction with the ECM components leading to an increase in the invasiveness of trophoblast cells. This is associated with an increase in the expression and activity of different kind of proteases along with a decrease in the expression of their physiological inhibitors. Additionally, mucin-type molecules like mucin 1 and podoplanin have also been shown to be involved in the regulation of trophoblast invasiveness. Expression of these effector molecules are regulated by the controlled expression of hormones, cytokines and growth factors of maternal as well as fetal origin. Further, enhancement of understanding about the molecular basis of regulation of early invasion at the feto-maternal interface by interplay of cytokines, adhesion molecules and proteases would help in improving the success rate of embryo implantation following assisted reproductive technologies.

During pregnancy, the maternal immune system is presented with the major challenge of maintaining a state of tolerance towards the allogeneic fetus, yet retaining the ability to mount an effective response to pathogens. Dendritic cells (DC) are bone marrow-derived professional antigen presenting cells critical in promoting immune responses and preventing autoimmunity. DC accumulates in the uterus during early stages of gestation, where micro environmental signals drive their maturation and determine their tolerogenic or immunogenic potential. Most importantly, DC subsets have recently emerged as important regulators of angiogenic and vascularization responses, which constitute a hallmark of successful implantation and pregnancy. This chapter discusses current aspects of DC biology at the fetal-maternal interface, focusing both on their classical role as promoters of tolerance or immunity; as well as the importance of their interplay with other components of the maternal immune system (i.e, NK cells) for the maintenance of pregnancy. A better understanding of the molecules and mechanisms modulating DC functions during gestation will provide important insights in reproductive medicine.

In this relatively short review, after recaling the immunotrophism theory and the Th1 /Th2 paradigm, and the fact that a major discovery in the field was that “immunologic” molecules are produced by cells of the reproductive tract of non-immune lineage, we try to summarize the main cytokines involvement in pregnancy, though redundancy and chaos like functions makes it sometimes impossible to ascribe a defined role to a single cytokine or even cytokine family.

Every ninth couple in Europe and USA is affected by implantation disorders and pregnancy wastage and majority of pregnancy losses occur before or during implantation. Therefore, understanding the cross talk between fetal and maternal components before, during and after their confrontations remains a major challenge. Human implantation may be described as a three steps process starting with the apposition and adhesion of a competent blastocyst to the endometrium epithelium and continuing by an extensive invasion throughout the first trimester of pregnancy in a receptive endometrium. The complex very highly reciprocal orchestrated process of human implantation leads to the essential construction of a haemochorial placenta. This chapter will detail the Human particularities of the implantation beginning by a maternal and paternal local preparation, a switch of the local immunity to establish transiently a local environment of immune tolerance. We will detail the role of hormone, cytokines, growth factors as well metalloproteases and transcription factors within this complex and evolutive dialogue.

Pregnancy is a unique and well-choreographed physiological phenomenon that involves dynamic maternal and fetal dialogue. Local immune tolerance, angiogenesis, cytokine and hormonal balance, cellular and molecular mimicry, genetic and epigenetic as well as environmental cues influence the pregnancy outcomes. Adverse pregnancy outcomes are a consequence of impairment of more than one of these factors that results in adaptation failure. In this chapter, we propose a two hit hypothesis for adverse pregnancy outcomes (Fig. 1) with particular focus on gene-environment interactions, as we understand them through the prism of interleukin (IL-10) and a decade of research with IL-10^-/- mice.

Uterine-natural killer (uNK) cells are a transient and dominant leukocyte in the uterine mucosa playing a key modulatory role at the maternal-fetal interface to support successful pregnancy. Despite having common bone marrow precursors and phenotypic similarities to circulating blood (c) NK cells found in the lymphoid organs and other mucosa, research has established that uNK cells in the uterine mucosa are a pregnancy-specific subset of NK cells. The ontogeny and phenotype of uNK cells inevitably raises the question of what role an innate immune effector cell containing a full set of cytolytic mediators plays in pregnancy. Extensive contributions from several laboratories have confirmed that human and mice uNK cells produce cytokines and growth factors for adequate uterine angiogenesis and vascular remodeling, control of placental growth, and maintenance of the decidual reaction to benefit the pregnancy. Undoubtedly, uNK cells are critical but not essential for successful pregnancy. Conversely, the expected cytotoxic activity of uNK cell seems to be suppressed in normal pregnancy, yet experimental approaches in mice points to the ability of these cells to have their inherent cytotoxic innate immune response triggered. Therefore, there is strong evidence to support uNK cell’s “reviled and revered” behavior in pregnancy. However, whether uNK cells dual role in the pregnant uterus is the result of a single multifunctional cell, or multiple uNK cell subsets remains as a challenging question in reproductive immunology.

The successful embryo implantation and development in humans and rodents are dependent on a tightly choreographed dialogue between maternal and fetal milieu, involving cross talking cells, cytokines and hormones. This dialogue involves the endothelial cells, stromal cells and leukocytes in the endometrium from the maternal side, and trophoblast cells from the embryo side culminating into a complex signaling network. Unscheduled deregulation of these signals could result in pregnancy complications. An intriguing aspect of this dialogue is the participation of uterine Natural Killer cells (uNK), a lymphocyte population that accumulates in the uterine microenvironment specifically during pregnancy. uNK cells differ from their peripheral blood counterparts both in humans and rodents by virtue of high granule content, low cytotoxicity, and production of cytokines. Although there have been suggestions for the involvement of NK cells in programming of early pregnancy loss, a debate still continues to assess their role as a friend or a foe to pregnancy. In this chapter, we discuss the importance of phenotypic and functional aberrations and their association with abnormal pregnancy outcomes.

The vacuolar ATPase (V-ATPase) is one the family of multimeric proton pumps involved in a wide variety of physiological and immunological processes. We have identified that the novel V-ATPase protein, i.e., a2 isoform of V-ATPase (a2V) appears to be a crucial molecule that helps facilitate maternal immune tolerance of the conceptus in the early pregnancy. But the origin and regulation of maternal immune tolerance is still unclear. From the beginning of pregnancy, sperm cells acquire hyper activated motility as they ascend the female reproductive tract during coitus. This enables sperm to overcome barriers and penetrate the cumulus and zona-pellucida surrounding the egg. This crucial process is called as capacitation. We have demonstrated that the capacitation of sperm induces the expression of a2V, leukemia inhibitory factor (LIF)), IL-1β, and Tnf-α in the sperm. Capacitated sperm also releases a cleaved N-terminal domain of a2V, (a2NTD) which upregulates the gene expression of LIF, IL1-β, Tnf-α and monocyte chemotactic protein-1 (Mcp1) in the uterus. During coïtus the male partner delivers semen which induces an inflammatory response in the uterus. This event is another component of the capacitation of sperm. Given the critical role that the release of the a2V subcomponent a2NTD from the capacitated sperm and its involvement in the expression of inflammatory cytokines; there is strong evidence that it is an essential molecule for induction of the required inflammatory response at the onset of pregnancy.

Human preimplantation embryos secrete a number of soluble factors into their environment, be it in vivo or in vitro. In vivo, these signals are fundamental for survival and implantation of the blastocysts. In vitro, during an assisted reproduction treatment, embryo-derived signals may be detected in the conditioned culture media and might serve for the estimation of embryo quality and its capacity to implant. Furthermore, the same fundamental soluble factors may be added to preimplantation embryo culture media or instilled into the uterus during embryo transfer. Several molecules have been detected in conditioned embryo media. The available literature about the most prominent factors, HLA-G, interleukins, hCG, PAF, leptin, SP-1, EPF, and Wnt beta catenin, are reviewed in this article. Several published results are contradictory or are based on doubtful analyses, which detect protein concentrations in the media which exceed the weight of the entire blastocyst. This review discloses the littleness of the current knowledge about the human embryo secretome, the difficulties of analyses and the need of further investigation.

Interferons have antiviral, antiproliferative and immunomodulatory effects on immune responses to defend the body against viral infections and malignant cells. The type I interferon family includes interferons alpha (IFNA1-IFNA10, IFNA13, IFNA14, IFNA16, IFNA17 and IFNA21), interferon beta (IFNB), interferon delta (IFND), interferon epsilon (IFNE), interferon kappa (IFNK), interferon tau (IFNT) and interferon omega (IFNW1-IFNW3). Interferon gamma (IFNG) is the only known type II interferon. Of the type I interferons, IFNT is expressed by mononuclear trophectoderm cells of ruminant conceptuses and IFND is expressed by equine and porcine conceptuses to affect pregnancy recognition and the uterine environment at the peri-implantation stage.

The pig conceptus also secretes IFNG during the peri-implantation period, but its role is not known. It is clear that interferons secreted by conceptus trophectoderm and/or immune cells recruited to the site of implantation of blastocysts during early pregnancy affect mechanisms for establishing the window of implantation as well as uterine acceptance of the conceptus, and placentation in many, if not all, species of mammals. This conserved trait of the mammalian peri-implantation period involves secretion of type I and/or a type II IFNs by trophectoderm cells which induces and/or enhances the expression of interferon stimulated genes in a cell-specific (spatial) fashion. Ruminant IFNT is the sole interferon so far identified as a signal of early pregnancy. But interferons produced by the conceptus or uterine immune cells of other species likely affect the peri-implantation uterus as well as endometrial decidualisation, and placental growth and development critical to successful outcomes of pregnancy. This review will highlight current knowledge of interferons that may affect pregnancy outcomes in humans, domestic animals and rodents.

The early phase of pregnancy is characterized by an inflammatory-like process and vascular remodeling that occur in decidua and are associated with hormonal changes. Extravillous trophoblast and NK cells present in decidua are responsible for these changes that are also contributed by the complement system. Complement activation occurs in physiologic pregnancy at decidual level as a result of tissue remodeling. Soluble and cell surface expressed complement regulators protect decidual endothelial cells (DECs) and trophoblast from complement attack that may lead to tissue damage in normal pregnancy. The recent report that preeclampsia is associated with mutations in the genes encoding for some of the complement inhibitors supports the important role of these proteins in the protection of the feto-placental unit. Control of complement activation can easily be overcome in the presence of complement-fixing antibodies directed against β2-glycoprotein I responsible for fetal loss and growth restriction.

Complement components synthesized by several decidual cells including trophoblast, DECs, and macrophages serve a defense function against infectious agents and promotes the removal of apoptotic cells. More, the complement system was recently found to contribute to placental development. Particularly important in this regard is C1q which is expressed on the surface of DECs and acts favoring the adhesion of endovascular trophoblast to the endothelial cells. Extravillous trophoblast is another source of C1q which binds to extracellular matrix and promotes trophoblast migration through the decidua. Unremodeled spiral arteries are surrounded by trophoblast cells that manifests reduced expression of C1q with important implications in preeclampsia characterized by reduced vascular remodeling.

Infections influence pregnancy by gaining access to the pregnant reproductive tract, infecting the placenta, the chorioamnion and the decidualised uterus. The negative impact pathogens can have during gestation is thought to involve innate immune responses aimed at the microbe, leading to excessive inflammation or apoptosis at the materno-fetal interface. Studies on the mechanisms of such actions have focused recently on the innate immune pattern recognition receptors (PRR), specifically, Toll-like receptors (TLRs) and Nod-like receptors (NLRs). These are now thought to play an important, if not a key role in infection-related pregnancy complications. Thus, inappropriate or inadequately controlled TLR and NLR-mediated reactions by the placenta and other gestational tissues may link infection with adverse pregnancy outcome. Understanding the regulation of TLR and NLR expression and function at the maternal-fetal interface in both normal and pathologic pregnancies is, therefore, critical for the development of better predictive and interventional strategies for women at risk of infection-associated adverse pregnancy outcomes. This chapter will review the current knowledge on the involvement of TLRs and NLRs at the maternal-fetal interface, and what the consequences of their function are on pregnancy outcome.

In this review, we first discuss the very concept of tolerance and then place it for the fetal allograft in the historical perspective of Sir Peter Medawar citation classic. We then wonder if there is really tolerance in the mainstream immunologist sense, and recall the also classic, but too often forgotten, experiments of Beer and Biillingham We also discuss the limits (in fact recognized in the papers, which is too often neglected) of experiments using weakly immunogenic tumors. Back somehow to Billingham, Head, and Beer notions, we then show that the maternal immune system "senses» the fetal allograft and is active, and that such activation, especially of the innate immune system, is needed for successful pregnancy. The data are then replaced in a modern perspective, and limits of "old" concepts, including my own, are reexamined and challenged.

In this brief sub-chapter we review first quickly pregnancy specific proteins (which were at the time seen in a context of general dampening of maternal immune response) to discuss then anergy inducing placental factors and exosomes. We finish by dealing with placenta integrated retroviruses, and their immunosuppressive properties.

In a within-species mating of two histoincompatible individuals, the semiallogenic embryo may be ‘rejected’ by maternal defense mechanisms. In a danger environment, the more histoincompatible embryos survive due to activation of maternal immunoregulatory cells, particularly Foxp3⁺ Treg cells, which are present at the implantation site. The CD200 tolerance signaling molecule that is expressed by fetal trophoblast cells and by cells in decidua appears to play an important role in activating a variety of regulatory T cells, and in suppressing macrophage pro-inflammatory mediator production. CD200 may be present in a membrane bound and soluble form. Whilst αβ TCR⁺ CD4⁺ Treg cells may be generated and activated in situ via maternal antigen-presenting cells in decidua, at and shortly after the time of implantation, CD8⁺ Ts appear important and these may infiltrate to the surface of the implanting embryo and produce soluble FGL2 (fibroleukin) in response to direct recognition of embryonic Class I MHC + peptide molecules; soluble FGL2 may act via FcγRII to suppress inflammation and immune cell activation. Although cytokines such as fibroleukin may arise.

Regulatory T cells emerged in the last years as key players in allowing fetal survival within the maternal uterus. They were shown to be a unique subpopulation of T cells expanding during human and mice pregnancy. However, there is now consensus that surface phenotypes of human and mouse Treg cells are not exactly the same. While mice Treg cells seem to be homogenous and exhibit regulatory function; human FOXP3⁺ Treg cells show more heterogeneity, containing suppressor and non suppressor subsets.

Regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile. Their periodic accumulation is accompanied by matching fluctuations in uterine expression of several chemokines, and the participation of immunological factors which play a role in the recruitment and retention of regulatory T cells.

This process also requires the adequate role of additional factors, like galectin-1, responsible of an adequate induced tolerance during pregnancy. Similarly, CTLA-4 expressed on Treg cells was shown to up-regulate IDO expression on decidual and peripheral blood dendritic cells and monocytes by the induction of IFN-gamma production.

While in normal decidua a functionally unique regulatory lymphocyte subset exists, decidual tissues from women suffering from recurrent spontaneous abortions (RSA) show a decreased regulatory activity, associated with a harmful role of Th17⁺ cells in rejecting conceptus antigens, and a decreased expression of IDO.

We also discussed the classical and the trans-signaling pathway of IL-6 signaling in modulating the induction of FOXP3 in women suffering from RSA.

During the early phases of pregnancy, natural killer (NK) cells are the predominant lymphoid cells in the uterus. Uterine NK (uNK; decidual NK) cells contribute to vascular formation and placentation, and play an important role in induction of tolerance toward the fetus allograft by interaction with regulatory T (Treg) cells, dendritic cells (DCs) and CD14⁺ monocytic cells.

On the other hand, uNK cells have been shown to induce abortion by attacking the fetus or Placenta.We propose that CD25⁺IL-10⁺NK cells play a pivotal role in successful pregnancy and granulysin⁺ NK cells attack extra-villous trophoblasts (EVTs), causing their death due to apoptosis. A deeper understanding of the balance between cytotoxic NK cells and regulatory NK cells during pregnancy may increase understanding of normal pregnancy and complicated pregnancy.

Immune attack of the conceptus at implantation is suppressed predominantly by the actions of T regulatory (Treg) cells and deficiency in these cells is linked with unexplained infertility, miscarriage, and preeclampsia. The pathways by which Treg cells originate and the factors that control their ontogeny and recruitment into the implantation site are now being explored. Experiments in mice show that male seminal fluid plays a pivotal role in expanding the size of the inducible Treg cell pool after every coital event, in readiness for potential pregnancy. The cytokine TGFβ which induces Treg cells, as well as male alloantigens, are abundant in seminal fluid and exposure of female tissues to seminal fluid initiates a sequence of events causing Treg cells to be recruited into the endometrial tissue. This pathway depends on female dendritic cells that take up seminal fluid antigens and traffic to local lymph nodes to cross-present antigens to both CD8+ and CD4+ T cells, which in turn circulate via the blood to be sequestered back into the endometrium. Thus, agents of both male and female origin in the peri-conceptional environment are important determinants of maternal immune tolerance and ultimately the progression and success of pregnancy. Components of this pathway are present in the human genital tract, and recent studies show seminal fluid activates immune cells in the cervix and seminal fluid TGFβ together with E-series prostaglandins play an important role in triggering this response. Defining how mechanisms of tolerance induction occur in women will be important for informing development of new therapies for pathologies of pregnancy that have an immune aetiology.

Progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss. Although a plethora of key functions and pathways affected by progesterone have been identified, there are still not sufficient diagnostic methods to precisely identify the groups of patients that would benefit from progesterone-treatment. We review the progesterone-induced genes and pathways, which control the process of endometrial receptivity as well as decidualization, and shape the immunological microenvironment at the materno-fetal interface. Recent clinical data suggest a possible beneficial effect of progesterone in the therapy of threatened miscarriage; still, further, larger, randomized controlled trials on the effect of progestogens on the treatment of threatened miscarriage are needed.

In pregnancy, the maternal immune system is regulated to tolerate the developing semi-allogeneic fetus. Systemic immunological changes can be detected which were historically described as being biased away from a graft rejecting ‘type 1’ pro-inflammatory phenotype, and towards a more tolerising B cell/antibody driven ‘type 2’ anti-inflammatory cytokine immunity. This hypothesis is now considered to be too simplistic and has been adapted in the light of more recent research. It is now apparent that normal pregnant women actually show mild systemic inflammation, when compared to non-pregnant women, although there is still a skewing of immune responses towards ‘type 2’. In this chapter we discuss the clinical and experimental evidence for these changes, which may be induced by a multitude of factors secreted from the placenta into the maternal blood These factors include cytokines, hormones, HLA-G, danger molecules and extra cellular vesicles from the syncytiotrophoblast layer. They interact with both the immune and endothelial systems and contribute to a healthy pregnancy. Deregulation of these factors may lead to the development of pre-eclampsia, in which there is excessive maternal systemic inflammation along with endothelial dysfunction, endangering the lives of both mother and baby.

In this chapter, we review the main characteristics of 3 murine abortion models, the Mus Caroli Mus Musculus system [which proved to be NOT of immunological origin], and the CBA x BALB/c, CBA x DBA/2 model, as well as the B10 x B10.A model. We also envisage the across species Donkey in horse system.

This short review first defines epidemiology of RPL, and then examines the various parameters of importance for RPL such as prevalence, prognosis, familial aggregation, partner specificity, perinatal outcome, as well as those parameters which affect biomarkers of interest in RPL Research.

After re-introducing the topic, this review examines briefly the present status of the various treatments proposed for immunologic recurrent pregnancy loss and implantation failure IVIG; Intralipid, LIT, G-CSF, Corticosteroids, Anticoagulants TNF-α blockers, and then show progress and future directions in the conclusion.

This chapter briefly summarizes the reasons why the immunotherapy approach can be recommended for recurrent pregnancy failure.

This chapter briefly summarizes the reasons which I put forwards at the time to discard tmost of the immunotherapy approach for recurrent pregnancy failure, and the recent developments which make me partly revise my opinion, since a safe and effective treatment might have been proposed.

Trophoblast cells have the critical responsibility of invading into the endometrium in order to anchor the embryo to the maternal endothelium and for establishing connections with maternal blood supply to obtain adequate blood flow and nutrition from the mother. These processes involve complex and intricate communication between trophoblast cells and the endometrium.

An interesting dilemma is presented to the organism during early pregnancy; on the one hand, the trophoblast should certainly invade maternal tissues well enough to anchor the conceptus and seek an adequate maternal blood supply. On the other hand, this invasion should be monitored and modulated appropriately lest it become overly invasive. How is this balance maintained? Several cells and molecules have been implicated in promoting and restraining trophoblast invasion. This chapter reviews the process of invasion, and the cells, molecules and mechanisms that appear to govern this process.

The importance of optimal uteroplacental blood flow cannot be overstated; aberrations in uterine blood supply result in pregnancy complications such as intrauterine growth restriction (IUGR). This chapter reviews immunological aspects of IUGR and discusses possible contributions of the maternal immune system to IUGR.

Hypertensive disorders of pregnancy (HDP) represent globally 10% of human births and their major complication, preeclampsia, 3 to 5%. The aetiology of these HDP remains still uncertain, however major advances have been made these last 25 years. The defect of trophoblastic invasion encountered in preeclampsia, intra-uterine growth restriction and to some extent also preterm labour has been understood only at the end of the 1970’s. On the other hand, clinical and epidemiological findings at the end of the 20th century permitted us to apprehend that “preeclampsia disease of primiparae” may in fact well be the disease of first pregnancies at the level of human couples. Among the important advances, immunology of reproduction is certainly the topic where knowledge has literally exploded in the last decade. This paper relates some major steps in comprehension of this disease and provides a review of epidemiological studies on the “primipaternity paradigm”. It focuses therefore on the interest to follow these immunological works and their new concepts. It seems, at the beginning of the 21st century, that we are possibly closer than ever to understand the aetiology of this obstetrical enigma and also the pathophysiology of the global endothelial inflammation in preeclamptic women. In this quest, the immunology of reproduction will certainly come out as one of the main players.

Preeclampsia, the most frequent, serious, hypertensive complication of pregnancy, occurs in about 5 to 8% of all live-birth pregnancies in the United States. Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unknown. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. There have been numerous attempts to generate animal models of preeclampsia. An ideal animal model of this disease would exhibit all the symptoms seen in preeclamptic women: hypertension, proteinuria, endothelial dysfunction including glomerular endotheliosis, and imbalance of angiogenic factors. Finding a model that satisfies these criteria has been very challenging. In this chapter we will discuss new disease models that have been created to tackle this complex and devastating disorders.

In this chapter, Dr. Gleicher first examines how autoimmunity and pregnancy interrelate. In doing so, he equates the fetal semi-allograft to a mini renal transplant, and takes the reader on a journey of discovery, comparing allogenic organ transplants with pregnancy. He then tackles the preconception period, addressing the search for subclinical autoimmunity. The involvement of autoimmunity with implantation and early pregnancy syndromes follows, discussing in more detail the recently described “implantation rash” and explaining early pregnancy loss. The role of class II HLA compatibility is examined with rheumatoid arthritis as original example. Mid-pregnancy is examined, with attention to treatments of laboratory autoimmune abnormalities and autoimmune diseases. Late pregnancy is discussed as a final immune challenge to the maternal immune system due to large amounts of paternal antigens entering the maternal circulation. Microchimerism, consequence of bi-directional cellular traffic, is explained as essential for allograft tolerance. Since this chapter could be a book on its own, the reader is referred to relevant references at each stage, so that both neophyte and clinical practitioner can benefit from these pages.

The frequency of early in utero mother-to-child transmission (MTCT) is low even in the absence of antiretroviral therapy. One route of HIV-1 in utero transmission is the infection of cells at the materno-fetal interface. In fact the decidua is susceptible to HIV-1 infection. At the materno-fetal interface, decidual cells are in contact with the placenta, which can be infected in vitro by cellular contact with infected cells. Thereby, infected decidual cells or maternal blood cells could infect the placenta in vivo. However, several mechanisms involved in the control of HIV-1 infection have been described in the placenta and in the decidua. Notably, the balance of cytokine and chemokine expression profile influences HIV-1 infection. Other soluble factors, like hormones and antibodies, are involved in the control of the placenta infection. Finally, decidual immune cells, such as NK cells or T cells subsets, could also be involved in the control of HIV-1 MTCT. However their role in this context has not been studied yet. The understanding of these mechanisms of control is important for the development of new prevention strategies against HIV-1 transmission.

Infertility is an emerging health issue and the incidence is getting increased with a recent trend of postponing pregnancy to later in life. Unfortunately, approximately half of infertile couples remain unexplained, who often have clinical manifestations such as poor ovarian response and poor oocyte quality, failures of fertilization and embryo development, thin endometrium and inappropriate uterine blood flow, repeated implantation failures, and early pregnancy losses even with extensive treatment. Recent efforts to identify the underlying etiologies for these problems have revealed that a significant proportion of these women have immunological abnormalities such as autoimmunity, dys-regulated cytokine network, abnormal activation of innate immunity, increased Th1 immunity, and inherited or acquired thrombophilias. Glucocorticoids, intravenous immunoglobulin G infusion (IVIg), and heparin have been utilized for these patients and reported to improve reproductive outcome, especially when the treatment was given to women with immunological abnormalities and/or thrombophilia, but not if empirically given. Studies for NK cell levels and its cytotoxicity, Th1/Th2 cell ratio, ANA, APA, anti-thyroid antibodies, and genetic and acquired thrombophilia, can aid the selection of proper candidates for immune-modulation and anticoagulation treatment.