Human fetus being
The idea of the human fetus being a natural allograft is neither surprising nor new, as half of the fetal tissue is foreign. Such an incompatible structure could easily provoke an immune response from the mother's body, causing the fetus to be rejected. The reaction would be similar to that of organ rejection following a transplant, in which it is believed T-cells have a key role. Memory T cells migrate into these transplanted organs and initiate an immune response by secreting inflammatory cytokines (Page, Ford & Kirk, 2009), therefore what happens between a fetus and the mother is quite unique.
An article written by Germain et al. (2007) put forward a theory that used the maternal/fetal interfaces as a basis and studied systemic inflammation that occurred at these places, in normal pregnant women, and those with pre-eclampsia. The maternal/fetal connection creates two interfaces. The first is where the invasion of fetal cytotrophoblast into the deciduas meets the maternal natural killer cells (Hu et al., 2006). This retreats in the second half of the pregnancy. The syncytiotrophoblast comes into contact with the maternal blood system, creating interface 2. It is formed around 20 weeks into pregnancy and remains to become the key region of maternal/fetal contact.
When these interfaces are not constructed properly by the second trimester, pre-eclampsia can arise. It is a large contributor to worldwide morbidity and mortality of both mother and fetus (Messerli et al., 2010). Symptoms characterised with it are mainly hypertension and proteinuria, but also include acute haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Germain et al. suggested this disorder occurred when the inflammatory changes that take place at the two interfaces became unruly. Neutrophil infiltration has been suggested as a cause for inflammation in pre-eclampsia (Verlohren et al., 2009).
Germaine et al. focussed on cytokines, as they play in an important role within the exaggerated inflammation associated with pre-eclampsia. Generally, cytokines are attracted to traumatised regions within the body and promote the process of inflammation, by activating pro-inflammatory components, like macrophages and neutrophils (Velnar, Bailey & Mrkolj, 2009). In pre-eclampsia, cytokines TNF-α, IL-12, IL-18 and IFN-γ take part in what is known as the Shwartzman reaction. It is a dangerous reaction in an animal once endotoxin has been injected, and results in either a generalised or localised Shwartzman reaction (Motegi et al., 2006). However, pregnant animals do not need endotoxin to have a Shwartzman reaction. Symptoms for both pre-eclampsia and the Shwartzman reaction are similar, such as HELLP and hepatic necrosis and this is clearly explained by Germain et al. It has been suggested that in pre-eclampsia there is an increase in Th1 cytokines, but a decrease in Th2 cytokines (Verlohren et al., 2009).
The main stimulants for the systemic inflammation that occurred at the two interfaces interested Germain et al., and they homed in on cellular debris from the syncytial surface of the placenta, known as syncytiotrophoblast membrane microparticles (STBM). Syncytiotrophoblasts have a high turnover, and once gone through apoptosis they are shed into the maternal blood circulation (Carter, 2008).
Flow cytometry and co-cultures enabled Germain et al. to measure secreted and intracellular cytokine production by isolated and activated PBMCs, focussing more on the latter.
Comparing the results of cytokines from pregnant women to non-pregnant, there was a increase in secretion of TNF-α, IL-12p70, and IL-18 in the first trimester, followed by a decrease in all cytokines bar TNF-α, which plateaued in the second semester and was maintained throughout pregnancy.
Intracellular expression of both TNF-α and IL-12p70 did not change dramatically, with the only increase being for TNF-α, and decrease for IL-12p70.
IFN-γ was produced less throughout the pregnancy, with only the third trimester being significant. Intracellular production was also less, with greater inhibition in the CD56- lymphocytes than in the CD56+ NK.
Germain et al. found those with pre-eclampsia had virtually unchanged concentrations of secreted cytokines TNF -α and IL-12p70 compared to normal pregnancies. IL-18 was significantly increased compared to non-pregnant. There was a significant increase for intracellular TNF -α and loss of inhibition of IFN-γ in pre-eclampsia.
From the second trimester onwards, free STBM were detected, with significantly increased values in third trimester. It wasn't until the second trimester that there was significant binding of STBM, with a greater increase in the third trimester compared to the non-pregnants. Germain et al. stated free STBM was significantly higher in pre-eclampsia than in the normal pregnants, however no change was noted with bound STBM, compared to an increase that was seen in pregnant women.
Production of TNF-α, IL-18 and small levels of IL-12p70 and IFN-γ were detected within just 4 hours of co-culture of pSTBMs (cells taken from inside the uterus) and PBMC's from non-pregnant women. This too was shown by measuring the intracellular production. Small levels of IFN-γ production by both CD56+ and CD56- lymphocytes was stimulated by pSTBM.
The results confirmed there were differences between normal pregnancy and pre-eclampsia. It is thought the systemic inflammation is a secondary process to that of the localised inflammation that happens at interface 1. Shed STBM becomes detectable in the second trimester, due to the uteroplacental circulation opening. The immunosuppression of pregnancy may be overcome by the STBM acting as a counter-stimulus. In pre-eclampsia IFN-γ production was activated and this may have lead to IL-12 and IL-18 being produced in excess and creating an environment similar to that of the Shwartzman reaction.
This study holds vital information in relation to pre-eclampsia, but there are still unknowns. Messerli et al. used similar techniques to study the inflammatory characteristics of STBMs on human monocytes. They found activation of monocytes in both normal and pre-eclampsia pregnancy to be stimulated by STBM, with the higher the amount of STBM (as in pre-eclampsia), the greater the inflammatory response. Daher et al. (2006) genotyped cytokines in pre-eclampsia and found IL-10 polymorphisms were involved. Germain et al. obtained some crucial results, and put forward with other studies, a more conclusive correlation between cytokines and pre-eclampsia can be made.