Given the fetus is antigenically different from the mother and should provoke a rejecting immune response from her immune system, how the mother immunologically tolerates the fetus over the course of a ~9 month pregnancy remains an as-yet not fully resolved central mystery about the immune system.
Since the 1950s two common arguments for how the mother’s immune system tolerates a semi-allogeneic fetus assert that either the mother’s immune system is suppressed during the duration of the pregnancy or that the uterus and the growing fetus it carries are immune privileged.
A body that’s immunologically unprotected and unprotectable for ~9 months renders it in evolutionary terms essentially open sesame for pathogens to exploit, in which case we couldn’t possibly have even evolved. Fortunately though ever so slowly such evolutionarily untenable arguments are headed the way of the dodo.
An abundance of data instead shows that rather than immunosuppressed, immune systems of pregnant women function normally against any variety of immune stimuli including pathogens (). In fact, data now suggest that inadequate recognition of fetal antigens by maternal may even lead to failed pregnancy (2).
Further, passive transfer of antibodies from mother to fetus,, is a well-recognized feature of early life immunity. However, transfer of such protective antibodies represents only one side of a finely tuned double-edged sword, the other side being transfer of fetal antigen-specific antibodies such as IgG that could even be lethal for the fetus.
‘Why doesn’t the mother’s antibody IgG attack the fetus? Why are immune suppression drugs given in second delivery?‘
As for why a mother’s IgG antibody doesn’t attack the fetus, an antibody doesn’t attack randomly. A hallmark of the adaptive immune system, T and B cells, is they express somatically rearranged cell-surface receptors that bind to specific antigens. Such somatic rearrangement is the unique feature that endows the adaptive immune system with the capacity for anticipatory defense such that the body has circulating T and B cells capable of binding a seeming universe of antigens that a body hasn’t previously encountered.
Antibodies are secreted by B cells, which in this case would be a maternal antibody specific for a fetal antigen. Several steps are necessary to get to fetal antigen-specific maternal IgG.
For a mother’s B cell to bind a fetal antigen, it first needs to come in contact with it. In this case that would entail abnormal physiological changes such as fetomaternal or placental hemorrhage that would cause fetal red blood cells to leak into maternal blood, such physical contact being the trigger necessary to get the initial immune response going.
Well-known examples of situations where fetal antigens provoke a strong maternal immune response pertain to red blood cell antigens such asexpressed by the fetus but not the mother.
In any case, the initial antibody response is IgM. To instead secrete IgG antibodies against that antigen, the secreting B cell would need to get help from a T cell that bound a piece of the same antigen that the B cell bound in order to undergo class switch recombination,, a process called cognate T cell help where the help consists of specific receptor-ligand pairs binding on the surface of the interacting T and B cells as well as specific cytokines secreted by the T cell.
The requirement for cognate T cell help to make IgG antibody dramatically reduces the probability that first encounter with a triggering fetal antigen would yield a high enough antibody titer necessary to cause damage since T and B cell of any given specificity, i.e., specific for any given antigen, are typically of the order of 1 in a million. OTOH, repeated triggers (immunizations) from successive pregnancies across a well-known blood type difference are capable of amplifying the initial immune response and associated anti-fetal antigen IgG antibodies to above the threshold capable of causing damage (see figure below from).
This pattern is the reason for medical interventions with subsequent pregnancies in the case of such blood type mismatches.
1. Arck, Petra C., and Kurt Hecher. “Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health.” Nature medicine 19.5 (2013): 548.
2. Moffett, Ashley, Olympe Chazara, and Francesco Colucci. “Maternal allo-recognition of the fetus.” Fertility and sterility 107.6 (2017): 1269-1272.
3. Kumpel, Belinda M., and M. S. Manoussaka. “Placental immunology and maternal alloimmune responses.” Vox sanguinis 102.1 (2012): 2-12.