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- Nichole Gale
The systems controlling the implantation and acceptance of the genetically and immunologically foreign fetus within the maternal body have often been likened to that of an organ transplant, or the growth of a cancerous tumour. The fetus is ‘like a transplanted kidney’, in the way that it is ‘genetically different from the host’ and ‘must evade immune defences to avoid rejection’ (Quinn 1999). The fetus inherits ‘foreign paternally derived histocompatibility genes’, meaning that ‘there is close contact between two genetically disparate individuals’ within the maternal body (Warshaw 1983, p63). Thus, the fetus is often referred to as an allograft, an allograft being a ‘graft transplanted by an individual that is not genetically identical, but of the same species’ (Marieb 1998, p789). The subject of fetus acceptance and tolerance within the maternal body has triggered great interest and controversy, and the systems that allow the acceptance of the fetus are complex and varying. Internal gestation has involved ‘a wide range of adaptations of animals for retention of young within the body of the parent’ (Warshaw 1983, p63).
The human immune system includes many ‘cellular patterns that constantly exchange information’ to provide the body with the ability to ‘recognise foreignness or “non-self” in the form of antigens that enter our body’ (Warshaw 1983, p200). The recognition of antigens spark the inflammatory response, which must act with ‘minimum damage to the host’, in order to ‘eliminate the intruder’ (Warshaw 1983, p200). ‘Antigens are expressed by early human embryonic tissue’ (Loke 1978, p5), so it could be expected that the early human embryo would trigger an inflammatory response to rid the mother’s body of the ‘foreign body’. The exposure to non-self paternal antigens on the fetus ‘requires the adaptation of the maternal immune system to prevent the rejection of the allogeneic fetus without compromising the ability of the mother to fend off infection’ (Koch & Platt 2003).
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The immune system consists of an innate (humoral) and an adaptive (cellular) component, in order to combat potential pathogens. It has been suggested that the main immune response triggered by the fetus is the adaptive response, where there is antigen representation, followed by response instruction by Helper T cells (Quinn 1999). In normal pregnancy, progesterone suppresses the humoral response. This has been used to explain why some autoimmune diseases, such as rheumatoid arthritis that are under humoral effect, often improve during pregnancy (Quinn 1999).
Early work on immunological tolerance, conducted by Medawar, has been the foundation of further studies regarding the paradox of pregnancy. Medawar proposed three mechanisms that might together act to allow immune protection of the fetus. Two of Medawar’s earlier suggested mechanisms have since been proved to not actually ‘pertain during pregnancy’ (Aluvihare, Kallikourdis & Betz 2004). The first hypothesis was that there was ‘segregation of the fetal and maternal circulations’, or that ‘a barrier might form between the mother and fetus, preventing exposure of the maternal immune system to allogeneic antigens expressed on fetal tissue’, leading to immunological ignorance (Koch & Platt 2003). Medwar’s second hypothesis referred to the immunological immaturity of fetal tissue, and this allogenic immaturity acting to suppress the ‘expression of antigens that the maternal immune system might recognise as foreign and target for destruction’ (Koch & Platt 2003). More recent research has tended to focus on Medwar’s third hypothesis, ‘that the maternal immune system somehow ignores potentially immunogenic fetal tissue’ (Aluvihare, Kallikourdis & Betz 2004). Leading from this, there has also been much focus on ‘the means of inducing immune tolerance, the emergence of T cell suppression in mediating peripheral tolerance, the mechanisms mediating matererno-fetal tolerance and the role played by regulatory T cells in mouse and human pregnancy’ (Aluvihare, Kallikourdis & Betz 2005).
Koch and Platt (2003) suggest overlapping mechanisms such as ‘the formation of an anatomical barrier between mother and fetus, lack of maternal immune responsiveness, and a lack of expression of allogenic molecules by the fetus’ to account for the lack of fetal rejection. These mechanisms can help in beginning to understand how rejection is avoided, yet do not ‘completely explain how the fetus evades the maternal immune system’ (Koch & Platt 2003). Harding and Bocking (2001, p238) state that it was originally proposed that the maternal-fetal interface was perhaps ‘an immunologically privileged site’, or that there was a ‘generalised suppression of maternal immune response’.
Recent studies have challenged earlier theories such as these, and it has since been found that not only is there actual recognition of fetal alloantigens by the mother’s immune system, but that her body also responds to them. Fetal cells can be detected in maternal circulation, and ‘fetal tissue expresses MHC class I and class II and is antigenically mature’ (Aluvihare, Kallikourdis & Betz 2004). MHC are major histocompatibility complex proteins coded for by genes. Class I are found on virtually all body cells, whereas class II displayed only by cells that act in immune response (Marieb 1998). The understanding of the immune events and mechanisms occurring at the maternal-fetal interface are likely to help in the understanding of the ability of the fetus to survive within the maternal body.
Since Medawar’s proposed hypotheses, much focus has continued on fetal immune evasion mechanisms. As well as the three mechanisms above, suggested by Medawar, Koch and Platt (2003) explore a fourth mechanism, site-specific suppression. This refers to ‘local suppression of maternal immune responses at the maternal-fetal interface’ (Koch & Platt 2003). ‘Localised suppression at the maternal-fetal interface during pregnancy negates the need for systemic immunosuppression which could threaten the well-being of the mother’ (Koch & Platt 2003). Earlier studies suggested that trophoblast acted simply as a barrier between the mother and fetus, but it now seems that perhaps that it could have ‘diverse immunoregulatory properties controlling immune recognition, activation, and effector functions’ (Koch & Platt 2003).
It has been proposed by various studies that T cells play a major role in sustaining pregnancy. T cells are lymphocytes that mediate cellular immunity. ‘T cells with regulatory functions are potent suppressors of T cell responses and can protect tissues from T cell mediated destruction’ (Mellor & Munn 2004). Observations in experimental pregnant mice have shown that while pregnant, they tend to ‘overproduce a kind of T cell that reins in other immune cells that might target the fetus’ (Seppa 2004). In one study, conducted by immunologist Betz (Seppa 2004) it was found that ‘pregnant mice have double to triple the number of CD4+ CD25+ T cells, also called regulatory T cells, in their blood, spleen, and lymph tissue as do female mice that are not pregnant’. It has also been shown that in humans, levels of circulating CD4+ and CD25+ cells ‘increases progressively at each stage in human pregnancy starting from the first trimester’ (Mellor & Munn 2004).
It has been ‘demonstrated that Tregs (T regulator cells) have a key role in regulating maternal effector T cell responses to fetal alloantigens’ as maternal effector T cells seem to ‘pose a potentially lethal threat to the developing fetus in the absence of regulatory function mediated by maternal Tregs’ (Mellor & Munn 2004). It has also been speculated ‘that hormonal changes during pregnancy might provide one explanation for enhanced maternal Treg development during fetal gestation because pregnancy-associated hormones, such as progesterones, promote immunosuppression’ (Mellor & Munn 2004). In regard to the suppression of maternal immunity, it is still ‘unclear if Tregs directly or indirectly inhibit effector T cell responses to fetal alloantigens’ (Mellor & Munn 2004).
To further test the cells’ effect on pregnancy, 30 female mice were mated with males. 15 out of the 30 mice had fully functioning immune systems, whilst the other 15 mice lacked the regulatory T cells. While a slightly higher than normal number of healthy female mice became pregnant, none of the mice lacking T cells were able to become pregnant. It seems that the role of T cells remains unclear, but that further understanding ‘of the role of regulatory T cells might also lead to new treatments for suppressing rejection of transplanted organs and inhibiting autoimmune reactions, in which a person’s immune cells attack his or her own tissues’ (Seppa 2004). Mellor and Munn (2004) also suggest that the revelation that ‘maternal Tregs might help protect the developing fetus’ will have various implications, not only the possibility of offering alternative therapies to suppress immunity, but also possibilities for ‘improving pregnancy success rates in patients with problematic pregnancies’. Again, the effect of T cells on autoimmune diseases is referred to by Mellor and Munn (2004), ‘increased systemic Treg function might explain why some autoimmune syndromes, such as rheumatoid arthritis, go into remission during pregnancy’.
There has also been some discussion on the role of macrophages as immunoregulators of pregnancy. It has been claimed that most attention has focused on immune tolerance to the invading trophoblast and fetus, but Mor and Abrahams (2003) suggest that it is also important to ‘consider the function of the maternal immune system in the promotion of implantation and maintenance of pregnancy’. During implantation, apoptosis is necessary for ‘tissue remodelling of the maternal decidua and invasion of the developing embryo’ (Mor & Abrahams 2003). It has been sited that apoptosis is active in the ‘trophoblast layer of placentas from uncomplicated pregnancies throughout gestation, suggesting that there is a constant cell turnover at the site of implantation necessary for the appropriate growth and function of the placenta’ (Mor & Abrahams 2003). During implantation and invasion, it appears that a large number of macrophages are present in the maternal decidua and in tissues close in proximity to the placenta.
Originally it was thought the large numbers of macrophages were ‘to represent an immune response against the invading trophoblast’. Mor and Abrahams (2003) propose that this may not be the case, and that ‘macrophage engulfment of apoptotic cells prevents the release of potentially pro-inflammatory and pro-immunogenic intracellular contents’. Trophoblast cells carry proteins that are antigenically foreign to the maternal immune system. If these proteins are released as a result of cell death, it could initiate or accelerate immunological responses, ‘with lethal consequences for the fetus’ (Mor & Abrahams 2003). Therefore, the appropriate removal of the intracellular components by macrophages may be critical for the prevention of fetal rejection. Mor and Abrahams (2003) conclude that the ‘field of apoptotic cell clearance is beginning to flourish, and many questions remain unanswered’.
There is not just one mechanism involved in the immune regulation of pregnancy, but ‘multiple, diverse mechanisms that are likely sequential during gestation’ (Koch & Platt 2003). As humans have a much longer gestation period, and a more invasive placental anatomy, it is sometimes difficult to test in laboratory animals and apply results to humans, as there may be different mechanisms. But it is believed that mechanisms involved with the fetus can be utilised in the studies of rejection following transplantation. As Koch and Platt (2003) suggest, ‘knowledge of the immunoregulatory mechanisms of both the fetus and stem cells will help immunologists understand general mechanisms of tolerance and immune evasion, and will prove invaluable in the fields of organ and cellular transplantation’. It has been suggested that both studies in stem cells and fetal rejection can benefit each other and help in understanding of systems involved.
Pregnancy has also been said to have overall effects on the mother’s immune system and maternal defence against organisms. According to Creasy and Resnik (2004, p103) ‘numerous reports indicate that pregnant women have increased susceptibility to a variety of infections’. It is said that ‘there appears to be a trend toward increased susceptibility to viral infections, consistent with suppressed cell-mediated immunity and a relative decrease in Th1 (humoral/innate) responses during pregnancy’ (Creasy & Resnik 2004, p103). However, it also added that ‘more recent carefully analysed data do not indicate that maternal immunity is substantially impaired, and most pregnant women are able to adequately respond to most infectious diseases’ (Creasy & Resnik 2004, p103). Harding and Bocking (2001, p238) also claim that most studies tend to suggest that ‘maternal cell-mediated immunity is unchanged during pregnancy’.
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According to some experts, infertility, recurrent miscarriage, premature delivery and preeclampsia may all be linked to immunological abnormalities. It could be that some of these problems are due to ‘defective generation of Tregs during pregnancy’ (Mellor& Munn 2004). It is possible that methods involving in vitro expansion of Tregs could help in treating spontaneous immune disease syndromes. Koch and Platt (2003) also suggest that both adult and embryonic stem cells might use mechanisms similar to the fetus in avoiding rejection. ‘Future discoveries in the field of reproductive immunology will help us understand not only immune regulation during pregnancy, but also how immune responses towards organ and cellular transplants might be controlled’ (Koch & Platt 2003).
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