Introduction
Historically, it was thought that successful pregnancies require a dampening of the maternal immune system for fetal growth and survival, not unlike the need to suppress host immunity following organ transplant. However, we now understand that this is not exactly accurate. Although not often considered, the immune system is crucial in the protection of both the mother and fetus from embryonic implantation through pregnancy. It is now appreciated that intricate interactions and responses between the maternal immune system and fetus characterize the immunology of pregnancy, particularly at the maternal-fetal interface.
Maternal-fetal interface
The maternal-fetal interface facilitates vital nutrient transfer and waste removal between the pregnant person and fetus while also protecting the fetus from the extrauterine environment. Understanding the components of the maternal-fetal interface is crucial to fully grasp the dynamics of the immune system during pregnancy. These components of the maternal-fetal interface are necessary in ensuring the successful growth of a fetus during pregnancy.
Decidua: Derived from the uterine endometrium, the decidua serves as a transitional barrier which shields the embryo from maternal immune cells and provides early nutritional support prior to the development of the placenta. Decidual cells, made up of stromal and immune cells, are some of the first that interact with fetal antigens, ensuring immune tolerance to the fetus. The decidua also contributes to the invasion of trophoblasts (i.e., the main cells of the placenta and the first to develop from the fertilized egg), which is pivotal for placental development and remodeling of the spiral arteries, enabling the exchange of waste and nutrients through the placenta.
Fetal-derived Placenta: Formed from fetal trophoblast cells, the trophectoderm acts as a cellular barrier that protects the embryo from infection. Several morphological changes to the developing placenta rapidly take place following this, including the development of chorionic villi which establish primary contact between the placenta and maternal blood supply. The placenta is fully formed at the end of the first trimester.
Leukocytes: Leukocytes play a crucial role at the maternal-fetal interface and are recruited through cytokine signals from decidual stromal cells and trophoblasts. The three main leukocytes that that contribute to the interface are decidual natural killer (NK) cells, decidual macrophages, and regulatory T cells (Treg). Decidual NK cells are important for the formation of the decidua, implantation of the embryo, and remodeling of the spiral arteries. These cells also promote trophoblast invasion during placental development through the production of IL-8. Similarly, decidual macrophages contribute to tissue remodelling and blood vessel growth by producing soluble immune factors including vascular endothelial growth factor and matrix metalloproteinases. They also play a key role in the clearance of apoptotic trophoblasts and for protection of the fetus from infections. Finally, Treg cells foster maternal tolerance to fetal antigens by downregulating inflammatory responses, allowing for successful implantation by the embryo. These cells ultimately help maintain an environment conducive to fetal survival.
The immune system during pregnancy
As the field of reproductive immunology progresses new insights into the immunology of pregnancy have emerged, shedding light on the innate and adaptive immune systems.
Innate Immune System in Pregnancy
Numerous aspects of the innate immune system are modified during pregnancy, a subset of which are discussed below:
The complement system is involved in enhancing the function of phagocytic immune cells and antibodies to clear microbes and cellular debris in an organism. Several studies have reported increased complement activity during pregnancy. This activity is balanced by high levels of regulatory proteins, such as the complement inhibitor Decay-Accelerating Factor (DAF) in peripheral blood mononuclear cells, which functions by inhibiting the effects of complement activation. The balance of complement activation is necessary to prevent cases of preterm birth or pre-eclampsia (disorder of high blood pressure during pregnancy).
Neutrophils, cells that respond against microorganisms through production of toxic granules and reactive oxygen species, are also elevated during pregnancy, with a notable increase observed from the first trimester. During pregnancy, neutrophils undergo significant alterations in their functionality and exhibit retrograde transport of metabolic enzymes that ultimately limits their metabolic output which impacts their overall function. This functional change is likely necessary for a successful pregnancy, as increased neutrophil activity has been shown to impact placental development and can lead to pre-eclampsia.
The role of monocytes during pregnancy has also been extensively studied. In particular, numbers of intermediate monocytes, which are cells that display both inflammatory and phagocytic capacity, are elevated during pregnancy. It is hypothesized that the increase in numbers and activation markers of intermediate monocytes may be influenced by placenta-secreted molecules and overall maternal hormone changes. As pregnancy progresses, these activation patterns and cellular dynamics evolve, with studies supporting the upregulation of genes encoding for IL-10, a regulatory marker, and downregulation of genes encoding for IL-8, an activation marker.
Adaptive Immune System:
As with the innate system, various changes occur within the adaptive immune system that protects both the fetus and mother throughout pregnancy.
During pregnancy, a reduction in T cell frequency aligns with changes in T cell subsets, though the implications of these changes remain elusive. Interestingly, Treg populations were higher than helper and cytotoxic T cells during the first trimester, likely to facilitate successful embryo implantation, placental development, and early fetal growth. Although debated in the field, studies on Type 1 T helper (Th1) and Type 2 T helper (Th2) cells during pregnancy suggest that pregnancy maintains a prevailing Th2 state, supported by a rise in anti-inflammatory cytokines, a reduction in Th1-type autoimmune diseases, and increased incidences of Th2-type diseases. Despite this, the function of T cells during pregnancy is not entirely defined nor is it consistent between studies, underscoring the need for further research to understand the mechanistic role of T cell changes during pregnancy.
Maternal antibodies are required to protect the neonate immediately after birth. Yet, less known is that maternal B cells produce non-cytotoxic antibodies against paternal proteins that may be critical for a successful pregnancy, as these antibodies are absent in women who experience spontaneous miscarriage. Moreover, B cells have been shown to migrate to the placental decidua during the third trimester of pregnancy, hinting at their potential involvement in maintaining tolerance at the maternal-fetal interface. Analogous to Tregs, regulatory B cell (Breg) populations peak in the first trimester of pregnancy, presumably to suppress maternal Th1 responses, thereby fostering tolerance to fetal antigens. Research is ongoing to elucidate the mechanism behind the activation and expansion of Bregs during pregnancy.
Vertical Pathogen Transmission
Despite a highly protective immune system and physical barriers that develop during pregnancy to protect the fetus, vertical transmission, the transmission of infectious agents from an infected mother to her fetus, poses significant risks to fetal development. Vertical pathogen transmission can occur either before or after birth, however prenatal transmissions often lead to severe morbidity and mortality.
Toxoplasma gondii, Rubella, Cytomegalovirus, Herpesviruses, Parvovirus, HIV, and more recently Zika virus are collectively known as TORCH pathogens – a subset of microbes which have the capacity of causing teratogenic effects when transmitted from a mother to her developing fetus. These microbes have the capacity to access the intra-amniotic compartment where the fetus resides via placental damage or disruption, direct transmission through the placenta, sexual transmission and/or ascending infections. Infections can adversely affect the mother, fetus, and the placenta, potentially resulting in maternal sepsis, respiratory distress or even death. Importantly, vertically transmitted infections are known to cause birth defects (i.e., blindness, microcephaly, deafness), growth restriction, or death. TORCH pathogens further impact the placenta and can impair nutrient transport, exacerbating adverse outcomes for the pregnancy.
Despite our understanding of the outcomes of vertical transmission, the molecular mechanisms underlying microbial pathogeneses remain unknown, largely due to difficulties in modeling the complex architecture and immunology of the maternal-fetal interface. Current animal models fail to fully replicate human pregnancy. However, organoid models that contain both maternal and fetal cell types offer a promising technical model to explore the mechanism behind microbial pathogenesis and its impact on human pregnancies. Despite the complexity associated with mimicking the environment of pregnancy, ongoing research into the impact of infections at the maternal-fetal interface holds promise for advancing maternal and fetal health during pregnancy and beyond.
Baweleta Isho
