Maternal Immunological Tolerance of the Fetus

Introduction

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's 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 The 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's 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.

In contrast, when an organ or 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. For 40 weeks, a fetus is kept safe inside the amniotic sac within the uterus of the mother. Sustaining the uterine environment is crucial to this process.

The placenta acts as the lifeline for the unborn child, 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 layer 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, or 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 for specific action research since human trials are deemed 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 indicates that the fetal allograft only accepts indirect alloreactive T cells. 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." 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 examined methylated DNA (DNAm), 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 changed methylation levels more frequently in the first half of pregnancy, whereas the Th1 pathway methylation levels fluctuated more in the second half of the pregnancy. Treg pathways slightly differed throughout the trials but were not as notable as the T helper cells. This could provide insight into how DNAm can affect the presence of T cells in the body during pregnancy, as well as before or after.

Role in Transplantation

If it can be targeted, a specialized treatment option may be tested or 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 successful, there could be less need for vaccines and children, as well as 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 individuals which would drastically increase the long-term success rate for transplants and give a better quality of life to transplant recipients. The conclusion? Research and understanding of immunological tolerance of the fetus during pregnancy are still underdeveloped, but scientists continue to push for further development in 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 can 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.

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