A few weeks ago, actually maybe a few months ago now I was day-dreaming at my desk. I was supposed to be busy conducting experiments and reading research papers but I had a sudden burning question. Admittedly my question was rather odd and led me on a 2hr procrastination path. Don’t worry though, I managed to get something out it. I learnt something pretty awesome and it made me appreciate my precious mother, that oh-so-bit more.
I was transporting myself to 1987, while I was still in my mother’s tummy, I was wondering why my mum’s immune system didn’t go out on a mission to destroy me. I like to think it’s because she loved me to bits and yes, she still loves me no doubt! It seems a little odd though doesn’t it? We all know if we catch a cold, we will eventually get better because our immune system will find the bad bugs and eventually kill them off one by one. The reason is somewhat simple, those bugs are foreign and as a result your immune system does not recognise it as “self” and anything that is not “self” is eliminated. So with that rationale in mind it does seem a little confusing that when you have some growing inside you, that isn’t exactly “self” but rather 50% of “self.”
Lucky for me, I wasn’t the first person to think of this conundrum (gah, the problem of being a scientist after all the great discoveries have been made). Back in 1953, an immunologist by the name of Medawar, formulated three explanations for maternal-foetal tolerance. His first suggestion was that the physical separation between the mother and foetus allows for immunological tolerance, the second was that the foetal tissues were not mature enough to be recognised by the maternal immune system, and the last suggestion was that the maternal immune response was somehow inert. Although none of these suggestions were entirely accurate, it paved the way for considerable research into understanding the relationship between the mother and foetus in the context of immunity.
The maternal immune system turning a blind eye.
So first off, lets consider “the other 50%” – the paternal side. Given that the foetus is a product of both mother and father, you would assume the paternal molecular characteristics of the foetus would be the expected target for a maternal immune response. Some mothers report pregnancies riddled with complications which dissipate with a change in partners. In these cases it is believed the adaptive immune system recognises paternal alloantigens. An alloantigen is like a molecular fingerprint, and if it is not of “self” origin it is destroyed by the immune system. The real question however, is why doesn’t this happen all the time in every pregnancy.
The answer lies in foetal tolerance. You could consider this as the maternal immune system turning a blind eye to the developing foetus. One of the first experimental examples of foetal tolerance by the immune system was demonstrated in mice. By taking pregnant mice and grafting paternal tissue matching that of the male that impregnated the mouse, allowed the graft tissue to sustain. However, once the female had delivered her pup, the tissue graft would then be rejected. Furthermore, pregnant mice grafted with tissue from a third party male (i.e not the one that made the female pregnant) was rejected immediately. This demonstrated two important points, the first is that the immunosuppressive effect is specific to the paternal alloantigens and also this suppression is temporary in nature.
The implantation site of the foetus is richly populated by a number of different white blood cells with entertaining names like natural killer cells and T-cells to the more terribly named myelomonocytic cells. These are all components of the immune system. To ensure these components do not mount an attack on the foetus particularly the placenta the maternal immune system turns a blind eye in what is scientifically described as immunological ignorance. Turning off the immune system is no trivial feat and actually you wouldn’t want to turn it off entirely. It has to be a localised numbing of the immune system at the point of interaction between the maternal tissues and the foetus. One such example is the localised availability of the amino acid tryptophan. When tryptophan levels drop, it leads to a decrease in T-cell proliferation. This is achieved by the production of…wait for it… indoleamine 2,3 dioxygenase (IDO) in the maternal tissues and the invading foetus.
White blood cells are murdered.
A more spectacular example of localised immunosuppression is mediated by the foetus alone. Apoptosis is the word used to describe cellular suicide. Although, considering it solely as suicide is somewhat misleading as the process can at times be initiated by other cells nearby. This “death signal” is started by a molecular key called the Fas ligand which fits into a cell surface receptor called Fas. It’s a bit like having a self destruct button on the outside of the cell that can only be pressed by other cells that have the finger (or Fas ligand) to press it. In our context, white blood cells that would usually attack the foetus express this receptor and cleverly the foetus also expresses the Fas ligand leading the apoptosis of white blood cells or in this case the murder of white blood cells! This mechanism was discovered by using pregnant mice with mutations in the Fas receptor, which lead to an increase maternal white blood cells in the placenta followed by the destruction of foetal tissues, pretty neat.
Sometimes, just sometimes, foetal tolerance can be rejected.
I think the most interesting part of this molecular ballet is that intricate balance required to maintain a growing foetus. Whilst you need the immune system to be suitably suppressed for foetal survival there is always the off chance that a massive uterine infection occurs. In such cases, you need the immune system to ignite back to its former strength. Sadly, in these cases you get a spontaneous abortion – although this process is not well understood. The disruption of maternal-foetal tolerance is thought to arise from the presentation of paternal alloantigens in the frenzy of fighting an infection leading to an immune response not only directed at the infection but also the foetus. You might think the system is imperfect, but I like to take solace in knowing every baby has entered this world by dancing and playing molecular hide and seek with the notorious and powerful maternal immune system.
Trowsdale, J. & Betz, A.G., 2006. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nature Immunology, 7(3), pp.241–246.
Image credit to: http://pregnancy.baby-gaga.com/cartoons/cartoon22