Marilen Benner

CHAPTER 4 92 DISCUSSION Pregnancy poses an immunological challenge as semi-allogeneic fetal cells have to invade maternal tissue for correct placenta formation. Here, we provide an overview of the dynamic changes in lymphocyte subsets, shaping the gestational immune environment. We highlight a possible role for decidual B cells, whose potential contribution to healthy pregnancy is just starting to be considered. Our data reveal that B cells undergo phenotypic adaptations in the decidual tissues over time, which may be regarded as a physiologic component of healthy pregnancy. The possible relevance of B cells for healthy pregnancy is gaining attention (36). In mice, it was shown that the lack of mature B cells is associated with reduced litter size, decreased size of the embryos and higher susceptibility to prenatal infections (35). In women with common variable immunodeficiency, a condition associated with reduced frequencies of switched memory B cells in peripheral blood (37), an elevated risk for preterm birth or other pregnancy complications, such as PE, stillbirth or vaginal bleeding was observed (38). Recurrent miscarriage (39, 40) and PE (41) was also linked to alterations in the induction of B cell memory. Although there is no consensus regarding frequencies of systemic B cell subsets in pregnant women, healthy pregnancy, especially in its final stages, was consistently shown to be marked by a decrease in absolute numbers of circulating B cells (42-46). This may be explained by a decrease in B cell lymphopoiesis, as was shown in mice during gestation (47, 48), but it may also be due to a (re) distribution to local sites. Our observation that naive B cells in early decidual tissues increase in abundance and switch to a memory phenotype could be an indication that redistribution occurs. The question is, what purpose do these decidual B cells serve? Although there are indications that B cells may contribute to the inflammation required for the onset of labor (49), decidual B cells may well serve an additional purpose. By supervised and unsupervised analysis, we observed high frequencies of CD24 hi CD27 + (cluster I) and CD24 hi CD38 hi (cluster III) B cells in 1 st and 2 nd trimester decidua, cell types associated with IL-10 producing capacity, a cytokine involved in immune regulation (24). In our hands, decidual B cells produced IL-10, more than peripheral blood B cells, and even without prior in vitro stimulation. The latter may suggest that decidual B cells already received the necessary activation in utero . Unsupervised analysis revealed that these cell clusters, together with two additional clusters expressing CD24 and CD38 (clusters II and IV) are unique for decidua and not present in peripheral blood. These cells might represent a specialized tissue-resident B cell subset or they may be induced de novo through local interaction with fetal cells. Indeed, recent in vitro experiments point out that trophoblast cells have the capacity to upregulate IL-10 in B cells, underlining the impact of fetal cells on B cell stimulation during the peri-implantation period (50). Likewise, upon in vitro stimulation, especially B cells derived from 1 st trimester decidua produced IL-10. This might support the notion that B cell mediated IL-10 production is induced relatively early on in gestation, shortly after primary