Immune tolerance in pregnancy

When I'm talking about science, or listening to talks I put things in context of my field of interest; for me my "science jam" is development (aka embryology). And I'm not just talking about fetal development, I mean everything that contributes to the progression of fetal growth. One of those outside factors that is particularly interesting in the scope of this class is maternal immune tolerance. An entire non-self entity establishes residence for roughly 9 months and to top it all off they are messy house guests because they leave little bits behind (microchimerisms, we will discuss those later).

The developing conceptus is considered semiallogenic because it expresses both maternal and paternal genes.  Therefore, somewhere along the course of evolution eutherian (placental) mammals had to develop a mechanism to prevent an immune response directed at the fetus. 

To understand these mechanisms we have to consider a number of different aspects.  For one, the female reproductive tract is a non-sterlie environment that contains its own set of flora and is susceptible to infection by outside pathogens.  The first line of defense in the female reproductive system is the mucosal membrane that contains IgA and proteases that can defend against bacteria etc. but also has to be permissive to sperm.  This is the first step in the immune tolerance mechanism, because here the female reproductive tract has to make a choice about what invaders are welcome and which ones are not. 

So what are the players in the maternal immune system that are establishing tolerance?  I’m sure if you took a guess, you said Tregs.  And you are right!  In this case it’s pTregs, or Tregs that are induced in the periphery as opposed to tTregs that are induced in the thymus.  The pTregs are thought to establish tolerance at interfaces like the lungs, gut, and in the case of pregnancy the maternal reproductive tract.  While tTregs take on the task of preventing autoimmunity and maintaining immune homeostasis.  Interestingly, women with preeclampsia, a pregnancy-associated disorder, have fewer Tregs and increased Th17.  The pathogenesis of preeclampsia is unknown but the maternal immune system is likely to play a role.  Another maternal immune cell implicated in immune tolerance is the uterine natural killer cell (uNK).  NK cells normally exist in the periphery, and have similar roles to cytotoxic T cells, but are not of T cell lineage.  uNK cells, are less understood but it is known that they play a role in decidualization of the uterus in response to the normal menstrual cycle and they act as. During pregnancy they are thought to play a role in helping trophoblasts invade into the myometrium in order to gain access to the maternal circulation.  So if uNK cells act like cytotoxic T cells, what is going on to turn them from killers to helpers?

Well to answer that question we need to look at what fetus is doing in order to gain maternal immune tolerance.  Trophoblasts do no express MHC class I, and they are the first fetal cells that come in contact with maternal cells.  Trophoblast do however express non-classical HLA-C and a soluble HLA-G which may interact with receptors on NK cells to help down-regulate the normal cytotoxic response and steer the uNK cells to aiding in getting trophoblasts to the maternal arteries. 

There are some disease examples when immune tolerance is not established, such as Rh disease.  In this disease the mother produces IgG antibodies against the Rhesus D antigen located on the red blood cells of her fetus.  Like we discussed in class, IgG is the only maternal antibody to cross the placenta.  It occurs when the mother is Rh negative and the fetus is Rh positive.  It also occurs in subsequent Rh incompatible pregnancies, because of the placental tissue left behind (microchimerisms) after the first pregnancy enters the maternal circulation and evokes a IgG mediated response.  So it’s essentially like a vaccine, a little bit from the first pregnancy exposes the maternal immune system to an antigen, and then in the next pregnancy that antigen is recognized by memory cells and mounts a much larger immune response. 

What can we learn from immune tolerance in pregnancy? Interestingly, the immune tolerance mechanisms in pregnancy are very similar to the ones used in cancer progression.  So understanding immune tolerance in pregnancy not only gives us further insight into the immune system in general, it can also provide valuable context for understanding cancer progression.  The final figure shows the similarities between cancer and pregnancy progression.

Here are some helpful reviews If you want more details, as this post only scratched the surface of what’s currently known:

1)http://www.sciencedirect.com/science/article/pii/S0092867412007738

2)http://www.nature.com/ni/journal/v7/n3/full/ni1317.html

3)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770910/