Maternal Immunological Tolerance of the Fetus
The complex function of the mother’s immune system during pregnancy has baffled scientists for many years. It has been observed how the mother’s immune cells modify their response in order to function alongside the fetus’ developing immune system. The immunological interaction between the fetus and the mother has been compared to a transplanted organ in hopes of furthering scientific research into developing a more accurate and sustainable transplantation process.
“A successful pregnancy involves complex interactions between fetal trophoblasts and maternal decidual immune cells, which allow the embryo and the fetus to develop in the uterus while the mother’s immune system remains largely intact.””1 A fetus is often looked at in the sense that it is solely part of the mother; however, it is made from the genetic material from both the father and the mother which makes it foreign to the mother’s body. When comparing the fetus’ genetic makeup to a transplantation, scientists are referring to the genetic code and cells not matching the mother’s because of the “”donor”” (aka the father).
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How it works
In contrast, when an organ/tissue is transplanted from a non-identical donor, the Human Leukocyte Antigen complex of the host will initiate an immune response against the HLA proteins on the donated tissue. Therefore, the study of the mother’s immune tolerance to the fetus can be used to further understand how the body interprets and responds to antigens in comparison to the body’s response that would provoke rejection of an allogenic transplant. Sustaining uterine environment For 40 weeks, a fetus is kept safe inside the amniotic sac within the uterus of the mother.
The placenta acts as the life line for the unborn child and is responsible for nutrient and waste product exchange between the mother and the fetus. The outer surface of the placenta is embedded in the maternal decidua. The maternal decidua is a specialized stromal tissue level that is formed from the endometrium. Since the fetus and mother do not have direct contact, the placenta acts as the main source for T cell priming and is the primary source for a targeted immune event.
Maternal hormones are responsible for uterine secretory activity. Uterine Natural Killer cells (uNK) play a role in maintaining proper growth and development throughout the first trimester of the pregnancy. Regulatory T cells role Treg cells suppress the response of self-reactive CD4 T cells to their specific self-antigens.
They are present in the circulation of all people and are distinguished from other CD4 T cells by their expression of CD25 on their cell surface. Treg cells can suppress the proliferation of native T cells responding to self-antigens. They require contact between the two cells and the release of cytokines but do not have specific target pathogens.
While it is difficult to study the exact role of T cells during pregnancy, mice are commonly used to research the specific actions since human trials are unethical. From the mice trials, it was found that antigen presentation is exclusively mediated by maternal APCs and direct recognition of paternal MHC molecules by maternal T cells does not occur to an appreciable extent. This shows that the fetal allograft only accepts indirect alloreactive T cells.3 It is “”possible that induced Treg cells are generated from naive CD4+ T cells by antigens in semen, and the release of these same antigens from the placenta later in gestation mainly serves to bolster the expansion of the induced Treg cell population.””3 Hematopoietic stem progenitor cells are hypothesized to be the basis for immunological coverage in a developing fetus.
In one study, researchers compared how Th1, Th2, Th17, and Treg pathways differentiate throughout gestation. They looked at methylated DNA (DNAm), more specifically, the CpG site, to see if there was a correlation in the number of T helper and Treg cells present before, during the first half of pregnancy, during the second half of pregnancy, and post-partum. The results showed that Th2 genes in the first half of pregnancy changed methylation levels more frequently whereas the Th1 pathway methylation levels fluctuated more in the second half of the pregnancy.4 Treg pathways differed slightly throughout the trials but was not as notable as the T helper cells. This can provide insight into how DNAm can affect the presence of T cells in the body during pregnancy and before or after.
Role in Transplantation
There are multiple types of Treg cells which are made and activated specific ways. From the thymus, CD4+ T cells expresses the ?± chain CD25. Induced Tregs are present when an immune response is activated, and they are in charge of stopping the response once the pathogen has been effectively cleared.5 When a transplantation is being rejected, two phases emerge: the priming phase and the effector phase.
The priming phase is when “”activated dendritic cells (DCs) migrate from the graft site via the regional lymphatics to the draining lymph nodes and activate host T cells.””1 The effector phase is when “”activated T cells exit the lymph nodes and home via the blood to the graft, where they perform the effector functions that lead to graft demise.””1 Direct allorecognition involves the activation of about ten times more T cells and provides a substantial threat to the success of the transplant’s survival.
Given the limited research, many variables are left unknown. This causes controversy amongst the presented data and information. Since most of the research is performed on animals (mice) and is largely hypothesized, discussions are continually ensuing to try to further understand the immunological tolerance of the fetus during pregnancy. One of the uncertainties revolves around how the maternal blood bathes the trophoblasts that reside within the body of the placenta.
It is understood that this allows for placental antigens and other material to be shed directly into maternal blood to systemically modulate maternal immune responses; however, it is unknown whether this second interface can also serve as a point of placental attack by effector T cells.1 Another prominent question is the role of Tregs during pregnancy and their association with complications during gestation and/or afterwards.
It is suspected that decreased proportions of the Treg cells in the body are linked to spontaneous abortion, placenta previa, pre-eclampsia, etc. While it is known that the placenta is an immune modulator throughout pregnancy, the alteration that it induces in the mother is still under researched. It is suspected that the placenta acts immunologically at the implantation site and systemically.3 The fact that is works as a protective unit in order to keep the fetus safe is unique in an immune response since a typical reaction would be suppressive.
Understanding the immune response during pregnancy and how it relates to organ/tissue transplantation has a solid base of information but will require years of research before breakthrough evidence can fully support the claim. One idea, as presented in source 1, stated, “”anti-placental passive immunization or experimental infection strategies might provide opportunities to develop predictive human biomarkers for placentation and implantation defects.””1 Focusing on the location and mechanism of infection would be beneficial towards understanding how tropism of a virus affects the outcome of certain immune responses.
If it can be targeted, a specialized treatment option may be tested/become available for various infections. This can be used in the obstetric field as well as transplantations and other surgical procedures. Another question presented was “”is it possible to create antigen-specific tolerance to defined epitopes by immunization in utero and/or by oral feeding at birth?””1 If this is successful, there would be less of a need for vaccines and children (and adults) would be less likely to become ill from various diseases. This would also open up the possibility to “”program”” the immune system to not target specific HLA proteins when receiving a transplant.
Genetic testing can further this research to customize exact treatment plans for the individual which would drastically increase the long-term success rate for transplants and give a better quality of life to transplant recipients. Conclusion Research and understanding of the immunological tolerance of the fetus during pregnancy are still underdeveloped but scientists continue to push for furthering the development of studying the effect of the fetus on the mother’s immune system.
While the role of Treg cells is established, the relationship of their response in an allogenic transplant versus an allograft (fetus) is still being analyzed. Treg cells are an integral part of the immune response and hold the power to improve treatment options for patients in a variety of circumstances. The potential that these small cells contain will positively change the way medicine is practiced and taught. Therefore, the study of the mother’s immune tolerance to the fetus can be used to further understand how the body interprets and responds to antigens in comparison to the body’s response that would provoke rejection of an allogenic transplant.