Introduction to the immunology of pregnancy
Gil Mor
Abstract
Cases of recurrent abortion, implantation failure, and babies with hemolytic disease of the newborn still puzzle us with the question “why did your mother reject you?” Immunological rejection was introduced more than 70 years ago by Sir Peter Medawar, a Nobel laureate that recognized pregnancy as a semiallograft that escapes rejection. Medawar, in the early 1950s, acknowledged for the first time the unique immunological complexity of the maternal-fetal interaction and its potential relevance for transplantation. He described the “fetal allograft analogy” in which the fetus is viewed as a semiallogeneic conceptus that evades rejection. Over the next 50–60 years, research has focused on elucidating mechanisms of immune tolerance that could explain the fetal allograft paradigm. The inadequate understanding of the immunology of pregnancy has major repercussions on how we approach the treatment and prevention of multiple pregnancy complications. The challenging questions that we confront as reproductive immunologists include: (i) are pregnant women more susceptible to infectious disease threats, (ii) how does a viral infection affect the fetus and the pregnancy outcome, and (iii) are prophylaxis and treatment appropriate and beneficial for pregnant women? More than a decade ago, we introduced the concept that the immune system in pregnancy is a “unique complexity”1 since on one hand it has to tolerate the paternal antigens present in the fetus, while maintaining an active protective mechanism against microbial infections.2 In the last 10 years, we have witnessed major growth in our understanding of the immunology of pregnancy that has shaped the clinical relevance and approach to reproduction. To discuss some of the questions and new perspectives, we invited experts on the field to examine basic concepts and clinical challenges. The foundation of reproductive immunology consists of the question: how can the mother tolerate the fetus for a full 9 months? Medawar proposed three possibilities that have been extensively explored: (1) Isolation of the fetus from the maternal immune system (mechanical barrier); (2) immunological suppression of the maternal immune system; or (3) the fetus could be antigenically immature—invisible to the mother.3-5 As discussed by Dr. Petroff and Dr. Ding,6, 7 none of these previous postulations have proven correct. Therefore, it is critical to carefully review them. Dr. Petroff and her colleagues provide a historical overview of medicine and its impact on our understanding of immunology and pregnancy and how some concepts have taken years if not centuries to evolve.7 Dr. Ding and colleagues provide a new view of the mechanism associated with the adaptation of the maternal-fetal immune system.6 Dr. Liao's group describes new mechanisms of immune regulation that involve the expression of new immune check points.8 Dr. Timova and colleagues discuss the role of NK cells and the molecular mechanism regulating their differentiation and function.9 In the same view, Dr. Zhang and Li provide a clinical overview related to alterations on the regulation of NK cells that lead to pregnancy complications.10 The process of immune tolerance is discussed by Drs. Sun et al. and Dr. Petroff,7, 11 as well as by Drs. Morelli and Sadovsky12 who present a new mechanism of communication between the placenta and the maternal immune system. An intriguing aspect of the immunology of pregnancy has been the role of immune cells at the implantation site, which represent a high percentage of the cell types of the endometrium and increase during early pregnancy. Dissecting their phenotype and their role has been an active area of research. A fundamental feature of the immune system is to protect the host from pathogens. This function depends upon the innate immune system's capacity to coordinate cell migration for surveillance, and to recognize and respond to invading microorganisms. During normal pregnancy, the human decidua contains a high number of immune cells, the majority innate immune cells, such as macrophages, dendritic cells (DCs), natural killer (NK) cells, and adaptive immune cells such as CD4+ T cells, CD8+ T cells and regulatory T cells (Treg).13 These cells are not indifferent from the presence of the fetus and interact with the cellular component of the placenta, the trophoblast. Additionally, their presence was used as evidence of immune sequestration; however, work from us and many others has proved that immune cells at the decidua are a fundamental component for the success of the pregnancy.13-20 These cells play a unique role maintaining the balance between tolerance to paternal antigens, support of the developmental process of fetal growth and the protection against pathogens that could endanger the success of pregnancy. The role of NK cells, macrophages, and T cells is extensively reviewed in this issue.7, 8, 13, 21 From an immunological point of view, pregnancy was considered a monolithic process where the function of immune cells and the immunological environment are the same in the first, second and third trimester. However, we observed that dendritic cells are essential for the preparation of the endometrium for implantation by creating an inflammatory environment22, 23 leading us to change the concept that pregnancy is only an anti-inflammatory environment.1, 24 Every developmental stage demands a unique immunological environment that will provide support and protection. Implantation and early placentation requires inflammation, while fetal growth is associated with enhanced tolerance, therefore, requiring anti-inflammatory signals, and finally the process of parturition, the rejection of an aging organ (placenta), which requires an inflammatory environment.25 The transition from pro to anti-inflammatory status is essential for the success of pregnancy,26 and it is the result of the communication between the placenta and the maternal immune cells.8, 27, 28 Embryo-derived hCG is one of the first immune modulatory factors that change the phenotype of the signals present at the uterus.27 Additionally, several studies have shown that the trophoblast secretes multiple factors that modulate the differentiation of maternal immune cells, such as macrophages, from pro-inflammatory into anti-inflammatory phenotype.28-30 The role of the placenta as an immune regulatory organ differs from Medawar's original conceptualization of the immunology of pregnancy. Medawar's observation was based on the assumption that the placenta is an allograft expressing paternal proteins, therefore, under normal immunological conditions, should be rejected. While there is an active and very specific mechanism preventing a maternal immune response against paternal antigens, the trophoblast and the maternal immune system have evolved and established a cooperative status, helping each other for the success of the pregnancy. The placenta, through cytokines and hormones secreted by trophoblast cells, educate uterine maternal immune cells,31 and determines the immunological environment at the maternal/fetal interface, as well as at the maternal systemic immune system.32-35 Interestingly, many of the maternal immunological changes that take place during pregnancy remain after the delivery of the fetus, suggesting a long term effect of the pregnancy on the maternal immune system36 and another major difference from the original conceptualization of pregnancy as a host/graft immunological process. The second explanation proposed by Medawar was a generalized maternal immune suppression, similar to what is induced in transplant patients. However, from an evolutionary point of view, it is difficult to conceive pregnancy as an immune suppressed condition. Immune suppression would endanger the mother and the fetus against infections and dangerous environmental signals. There is no scientific evidence that can demonstrate immune suppression; instead, the maternal immune system is strong and capable of protecting the mother and the fetus. However, as discussed by Sun and Petroff,7, 11 there are specific mechanisms of tolerance to paternal antigens that are not associated with systemic immune suppression and have a long term impact on the maternal immune response.37 All these studies suggest that the process of tolerance during pregnancy resembles tumor-induced tolerance rather graft-induced tolerance. We discuss this aspect in this issue as well elsewhere.2, 6 The facts discussed might answer the question whether pregnant women are more susceptible to infectious disease threats. Clearly they are not, since there is no systemic immune suppression; however, there is no doubt that there are changes in the maternal immune system that will impact the global response to infectious disease threats, and those changes are influenced by the presence of the placenta and the fetus. Both are immunologically active and will impact the overall immunological response of the mother. In other words, the immunology of pregnancy is the result of the combination of signals and responses originated from the maternal immune system and the fetal-placental immune system. The signals originating in the placenta modulate the way the maternal immune system behave in the presence of potential dangerous signals (Figure 1). The second question of how does a viral infection affect the fetus and the pregnancy outcome is relevant in view of the reality that we confront with global pandemics. Although the maternal immune system and the placenta is well prepared to contain and control the majority of viral infections, as exemplified by COVID-19 pandemic, the impact on the immunological response of the normal development of the fetus is unknown. Dr. Adams Waldorf's group35 and Dr. Menon21 discuss the impact of pregnancy on viral responses and the Fetal Inflammatory Syndrome. Similarly, Dr. Ding and colleagues6 discuss novel mechanism of protection by the placenta against viral infections while preventing an exacerbated inflammatory response. Maternal Immune Activation (MIA) as result of viral or bacterial infection is thought to increase the risk for fetal developmental problems such as autism spectrum disorders (ASD), schizophrenia, and allergies as well as maternal mortality and pregnancy complications such as preterm birth.38 We developed an animal model of viral infection during pregnancy based on the exposure of pregnant mice to a murine herpes virus (MHV68)39-41 and observed that viral infection during pregnancy is responsible for modifications in the recognition and response to bacterial products leading to early termination of the pregnancy (preterm birth), fetal death and in some cases maternal mortality.40, 41 Furthermore, our preliminary studies showed that although we were not able to detect viral infection of the fetal tissues, a viral infection of the placenta can elicit morphological changes in the fetal brain associated with an inflammatory condition of fetal tissues40 very similar to the Fetal Inflammatory syndrome discussed by Dr. Manon.21 The consequence of these and other findings is the answer to question three: are prophylaxis and treatment appropriate and beneficial for pregnant women? The answer is certainly yes. Prophylaxis and treatments that prevent MIA are absolutely essential to protect the mother and the baby. Vaccinations during pregnancy offer triple benefits/protection: for the mother, the fetus and the future health of the offspring. In conclusion, understanding the process of the immunology of pregnancy has multiple implications: success of the pregnancy (overcoming infertility), protection of the mother and the fetus, and ensuring the future health of the mother and the baby. Immunological complications during pregnancy will not only affect the pregnancy but can impact future generations. The author declares no conflict of interest.