Microchimerism as a source of information on future pregnancies

Abstract

Small numbers of fetal cells cross the placenta during pregnancy turning mothers into microchimeras. Fetal cells from all previous pregnancies accumulate forming the mother's fetal microchiome. What is significant about microchimeric cells is that they have been linked to health problems including reproductive and autoimmune diseases. Three decades after the discovery of fetal microchimerism, the function of these cells remains a mystery. Here, we contend that the role of microchimeric cells is to inform the fetus about the likelihood that its genes are present in future pregnancies. We argue that, when genes are more likely than average to be in future maternal siblings, fetuses will send a fixed number of cells that will not elicit a maternal immune response against them. However, when genes are less likely to be in future maternal siblings, fetuses will send an ever-increasing number of cells that will elicit an ever-stronger maternal immune response. Our work can explain the observed clinical association between microchimeric cells and pre-eclampsia. However, our work predicts that this association should be stronger in women with a genetically diverse microchiome. If supported by medical tests, our work would allow establishing the likelihood of pregnancy or autoimmune problems advising medical interventions.

Keywords: autoimmune diseases; game theory; inclusive fitness; intra-genomic conflict; parent–offspring conflict; pre-eclampsia.

Figure 1.

Information and the fetal microchiome. We present a schematic of how (i) lower-than-average and (ii) higher-than-average diversity of mating partners impacts the genomic variability of the fetal microchimeric population. Panel (a) illustrates how the genome composition of the microchiome reflects mother’s mating diversity. Panel (b) illustrates plausible cell communication mechanisms transmitting information on future relatedness to siblings. Panel (c) illustrates cell–fetus communication mechanisms which condition the extraction of resources.

Figure 2.

Sketch of information accuracy outcomes when the number of fetal cells and maternal immune response to those cells coevolves. Panel (i) shows coevolution in mothers with lower diversity of mating partners where fetuses are more related to future maternal siblings. Panel (ii) shows coevolution in mothers with higher diversity of mating partners where fetuses are less related to future maternal siblings. Grey lines show combinations of fetal cells, y, and maternal immune response, z, that produce the same degree of accuracy, a, that is, contours of the χ(y, z) surface. Thick grey lines show the particular cases of no information χ(y, z) = 0 and perfect information χ(y, z) = 1. Grey arrows are orthogonal to contours and show the direction in which inclusive fitness increase is greatest ($\mathrm{\nabla }{w}_o$ for offspring and $\mathrm{\nabla }{w}_m$ for mother). Green arrows show the direction selection drives migration of fetal cells y. Red arrows show the direction selection drives maternal immune response to fetal cells z. Black arrows point in the net direction of evolution. Dots indicate equilibria and their area the amount of resources extracted. Thick green and red arrows show the best strategy of fetus and mother respectively from the current equilibria. Following dots and thick arrows, we find the coevolutionary outcome. When fetuses are more related than average to future maternal siblings (i) there is no conflict between fetus and mother and the outcome is perfect information from fetal cells that are tolerated by mothers. When fetuses are less related than average to future maternal siblings (ii) there is conflict and the outcome is an arms race between fetus and mother with fetuses sending an ever increasing number of cells and mothers mounting an ever stronger immune response to fetal cells.

Figure 3.

Sketch of resource extraction outcomes when information coevolves in fetus and mother. Panel (i) shows coevolution when fetuses are more related to future maternal siblings. Panel (ii) shows coevolution when fetuses are less related to future maternal siblings. Green lines show the optimal resources extraction (ORS) of maternal resources by the fetus a certain accuracy of the information. Red lines show the optimal resources donation of maternal resources by the mother herself. Green and red arrows show the direction selection drives the accuracy of information, a = χ(y, z), in fetus and mother respectively and the optimal resource extraction by the fetus $x_o^{\ast }$. Dots indicate equilibria with empty ones being stable and solid ones unstable. The dashed back line represents a hypothetical threshold of resource extraction that when crossed results in reproductive health problems. When fetuses are more related than average to future maternal siblings (i) there is no conflict between fetus and mother and the outcome is perfect information from fetal cells and lower extraction of resources by the fetus. When fetuses are less related than average to future maternal siblings (ii) there is conflict. If the fetus wins the conflict, the equilibrium lies near the optimal resource extraction with perfect information $x_o^{\ast }(r)$. If the mother wins the conflict however, the equilibrium lies near the optimal resource extraction with no information $x_o^{\ast }(\overline{r})$. When the forces between fetus and mother are balanced, the equilibrium lies between perfect and no information $x_o^{\ast }(r)>x_o^{\ast }(\hat{r})>x_o^{\ast }(\overline{r})$.

Figure 4.

Patterns of paternity and risk of experiencing pre-eclampsia. Panel (i) shows all possible patterns of paternity in three pregnancies. A represents the father of the current pregnancy while B and C are other possible fathers. Thus, pattern AAA corresponds to not changing father in the last two pregnancies while pattern ABC corresponds to changing father at each of the last two pregnancies. Intermediate patterns correspond to having two fathers only, with the same father in current and previous pregnancies in AAB, and the same father in the last two pregnancies in ABB. Panel (ii) shows the risk of pre-eclampsia relative to normal blood pressure corresponding to each paternity pattern. Medical data show a gradual increase in the risk of pre-eclampsia relative to normal blood pressure as the paternity pattern becomes more diverse. Dashed lines correspond to the bars in the 1 pregnancy category to allow comparison. Figure drawn using data from Robillard et al. [42].

Figure 5.

Outline of predicted outcomes of medical interventions. Panel (a) summarizes the predicted association between diversity of the microchiome and medical conditions. Panel (b) shows the effect of a medical intervention that reduces the genetic diversity of the microchiome by destroying all cell variants except one. Panel (c) shows the effect of a medical intervention that reduces the genetic diversity of the microchiome by supplying abundant copies of only one type of cell.