One of the key features of the immune system is the ability to recognize foreign pathogens, including viruses, bacteria, and anything else containing genetic material that is different from that of the host. After detection, the immune system launches an immune response to destroy the foreign material and prevent infection. In contrast to this, a normal pregnancy requires the maternal immune system to allow a fetus (that is genetically different from the mother) to grow and develop for nine months. So how does this happen?
Pregnant Woman. Image Credit: Prostock-studio/Shutterstock.com
Oocytes and spermatozoa are haploid cells, meaning they each contain only one copy of each chromosome. Upon fertilization, these haploid cells form a diploid zygote, where the maternal and paternal copies of each chromosome join in pairs. This means that the zygote is made up of 50% maternal DNA and 50% paternal DNA. This can be described as a semi-allogenic, or a semi-allograft- where some, but not all of the genetic material is the same. For the zygote to grow and develop for nine months, the immune system of the mother has to accept this foreign material and allow it to receive the nutrients it needs, at the expense of the mother.
The immune paradox of pregnancy was first described in 1953 by Peter Medawar, who worked primarily on transplantation. He observed that whilst semi-allogenic material could be rejected in the case of transplantation, during pregnancy the semi-allogenic fetus was able to survive for nine months. This phenomenon raised questions about how the immune system could act differently during pregnancy than under normal circumstances, with important implications for both the field of reproduction and transplantation.
Uterine Natural Killer cells
Since Medawar’s initial observations, research has uncovered much more about the cell types and processes involved in both immune responses and pregnancy, however, there are still some areas that remain unclear. Uterine Natural Killer (uNK) cells are a subset of NK cells that populate the membrane of the uterus and are thought to play an integral role in embryo implantation.
Implantation is a carefully regulated process, whereby the developing embryo must establish itself in the uterine membrane, or decidua. Trophoblast cells, which form the outer layer of the developing embryo, invade the maternal tissue to access the maternal blood supply. These cells later develop into the placenta, and act as an area of transfer for nutrients and oxygen from the mother to the fetus, and waste from the fetus to the mother. Under normal circumstances, the maternal immune system would recognize this process as dangerous, so clearly there is a specialized pathway through which this is allowed to happen.
KIR and HLA-C
The trophoblast cells that invade the uterine decidua express antigens called human leukocyte antigen C (HLA-C), inherited from the father, whilst uNK cells express killer-cell immunoglobulin-like receptors (KIRs). It is now thought that uNK KIRs recognize trophoblast HLA-C, and identify the embryo as being different, but not pathogenic- a phenomenon is known as immune tolerance. This recognition allows the uNK cells to carefully regulate the invasive process.
The extent to which invasion happens is particularly important; if it is not deep enough, the developing fetus may not receive enough nutrients and suffer from undergrowth, if it is too deep the developing fetus may receive too much and suffer from overgrowth- which can be dangerous for both the fetus and the mother.
The role of T-cells
T-cells are important players in cell-mediated immunity. It is now thought that paternal factors in semen initiate a shift in T-cell composition, ‘dampening’ the maternal immune response to provide a safe environment for the fetus to develop. This is largely due to the balance of T-regulator (Treg) and T17 cells. T17 is associated with a typical immune response, protecting the body from pathogens, whilst Treg is associated with immune suppression and tolerance.
It has been observed that particularly during early pregnancy, the balance is shifted towards a much higher proportion of Treg cells. The level of Treg cells decreases in later pregnancy, whilst T17 cells increase, which could be a factor involved in the onset of labor.
The immunology of pregnancy is a complex process that is not fully understood and is still being studied with great interest. It is important to note that the immune system is not completely ‘switched off’ during pregnancy, as this would put both mother and fetus at high risk of infection. Instead, the immune system is carefully modulated and altered.
Although many potential key interactions have been identified and hypotheses have been suggested, the exact mechanisms are still unclear. It is thought that failures of immune tolerance could be a factor in unexplained infertility and pregnancy loss, therefore understanding this process could provide pathways to interventions for patients suffering from recurrent miscarriage or infertility.
Understanding the mechanism by which the immune system can tolerate foreign material could pave the way to new immunotherapies, both for pregnancy and in other fields such as transplantation and transfusion.
Sources:
- Figueiredo, A.S. and Schumacher, A. (2016), The T helper type 17/regulatory T cell paradigm in pregnancy. Immunology. 148: 13-21. https://doi.org/10.1111/imm.12595
- Koopman, L. A., Kopcow, H. D., Rybalov, B., Boyson, J. E., Orange, J. S., Schatz, F., Masch, R., Lockwood, C. J., Schachter, A. D., Park, P. J., & Strominger, J. L. (2003). Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. The Journal of experimental medicine. 198(8), 1201–1212. https://doi.org/10.1084/jem.20030305
- Medawar PB. (1953) Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Society for Experimental Biology. New York: Academic Press.
- Moffett, A., Hiby, SE., Sharkey, AM. (2015) The role of the maternal immune system in the regulation of human birthweight. Phil. Trans. R. Soc. B 370:20140071. http://dx.doi.org/10.1098/rstb.2014.0071
- Papuchova, H., Meissner, TB., Li, Q., Strominger, JL., Tilburg, T. (2019). The dual role of HLA-C in tolerance and immunity at the maternal-fetal interface. Frontiers in Immunology. 10, 2730. https://doi.org/10.3389/fimmu.2019.02730
Further Reading