During pregnancy, the maternal immune and endocrine systems undergo significant adaptations in order to maintain immune tolerance towards the semiallogeneic fetus. Pregnancy-related hormones, such as estradiol, progesterone, and glucocorticoids, soar, and leukocyte subsets of the innate and adaptive immune response systems functionally engage in ensuring successful implantation of the embryo, placentation, and maintenance of pregnancy until term. Over the last two decades, a considerable amount of research has been devoted first to understanding the functional role of natural killer (NK) cells, dendritic cells (DCs), and T cells, and then to dissecting potential cross talk between these cells and pregnancy-related hormones, decidual stroma cells, and fetal trophoblast cells [1, 2].
It is now evident that immune responses against fetal antigens are suppressed by multiple pathways that lead to dampening of T effector cells, generation of regulatory T cells [3-5], and modulation of DC [6] and NK cell functions [7], along with epigenetic modifications of the decidual stroma [8]. Remarkably, the amalgamation of these pathways ensures pregnancy success, whereas single-cell subsets or markers are largely redundant, as learned from reductionist approaches of single-gene knockout or in vivo cellular depletion experiments [1]. This profound maternal adaptation to pregnancy has certain collateral effects on maternal health. These effects include both health advantages, such as amelioration of distinct autoimmune diseases, including multiple sclerosis (MS) [9], and disadvantages, such as increased risk for certain infections, including influenza virus [10].
Considering the relevance of maternal immunological adaptation during pregnancy to autoimmunity, infectious disease, and fetal health, the importance of understanding these changes has become increasingly clear. In this context, one leukocyte subset has largely been neglected in reproductive immunology: the B cells (Fig. 1). As critical, nonredundant players in the adaptive immune response, B cells mediate humoral immunity by producing antibodies; more recently, research has unveiled antibody-independent immune-modulatory functions of certain B cell subsets. These findings have resulted in a reclassification of B cell subsets based on their potential to secrete a distinct cytokine profile [11]. Hereby, B cells activate or suppress immune responses via their interactions with DCs, NK cells, and T cells [12, 13]. Furthermore, a wealth of evidence supports that B cell subsets can be functionally promiscuous, capable of maintaining health as well as aggravating immune pathologies [11, 14, 15].
B cell subsets within the innate and adaptive immune system that are modified during the maternal immune adaptation to pregnancy. Leukocytes of the innate and adaptive immune system include effector and regulatory T cells, monocytes/macrophages, NK cells, and DCs. Pregnancy-related hormones such as progesterone, estradiol, and glucocorticoids are involved in mounting this maternal immune adaptation. This adaptation ensures progression of pregnancy and immune tolerance of the allogeneic fetus, thereby promoting fetal and neonatal health. B cells are critical to postpartum health of the offspring as mediators of passive immunity via antibody transfer. Collateral effects of the maternal immune adaptation to pregnancy, which also involves the B cell response, encompass an altered course of autoimmune disease activity and reduced immunity against pathogens such as influenza A virus.
The recent publication by Muzzio and colleagues at the University of Greifswald in Germany has begun to close the gap in knowledge on the function and modifications of B cell subsets and their function during pregnancy [16]. In their study, the Greifswald group provides evidence that B cell development undergoes significant adaptations over the course of pregnancy in allogeneically mated mice [16]. These adaptations include a gradual reduction in numbers of pre/pro and, to a lesser extent, immature B cells in the bone marrow early during gestation, prior to the completion of placentation. These findings overcome a limitation of previously published evidence, in which a similar suppression of B lymphopoiesis during gestation had also been observed, but cells from different gestational stages had been pooled [17].
By midgestation, the Greifswald group observed a clear reduction in numbers of B cell precursors together with an increase in numbers of mature B cells, which together suggest an a reduction in B cell lymphopoiesis. Subsequent in-depth analyses of B cell development in the periphery unveiled a preponderance of marginal zone B cells in the spleen. Splenic marginal zone B cells can give rise to antibody-secreting memory B cells and plasma cells, which are required to deal with infections such as the influenza A virus. Hence, it is possible that mechanisms are activated to overcome potential limitations of maternal immunity associated with the observed B cell lymphopoiesis during pregnancy. The effectiveness of such marginal zone B cells will have to be tested in future studies, for example in models of influenza-related morbidity and mortality during pregnancy.
The Greifswald group also described a pregnancy-related decrease in serum levels of B cell-activating factor (BAFF), a cytokine that belongs to the tumor necrosis factor superfamily [18]. BAFF is a survival factor for autoreactive B cells, and hence reduced levels of BAFF may account for the reduced occurrence of autoreactive B cells and amelioration of MS during pregnancy [19]. Considering that maternal B cells are the source of antibody-mediated protective immunity for the newborn, insights on regulatory functions of B cells during pregnancy and the early postpartum period may not only be relevant to understand maternal immune adaptation to pregnancy, but also ensure neonatal health by protecting the newborn from infections [20]. In fact, mice lacking functional B cells are able to complete an uncompromised pregnancy, but survival of offspring is severely compromised because of the absent transmission of protective antibodies during the suckling period [21].
Taken together, the considerable lack of knowledge surrounding the role of B cells during pregnancy and the perinatal period is increasingly addressed in reproductive biology research over the last years [22-24] and the present work of the Greifswald group will likely foster additional studies. The emerging insights support the notion of a tailored B cell response during normally progressing pregnancies, which endows B cell subsets to promote fetal tolerance and concomitantly maintain maternal immunity (Fig. 1). The next milestones that need to be addressed include the clear-cut identification of the purpose of the observed B cell changes during pregnancy, for example by experimentally addressing their role in maintaining maternal immunity. In this context, the identification of an interaction between B cells and other leukocytes of the innate and adaptive arms of immune system, as well as pregnancy-related hormones, will also be critical. Furthermore, considering that B cell subsets can be functionally promiscuous, future research is needed to assess if pregnancy complications such as spontaneous abortion, preeclampsia, or intrauterine growth restriction are caused or aggravated by the failure to mount a tailored B cell response. Insights obtained from B cell-related research endeavors addressing these issues in the future may open exciting avenues for therapeutic B cell-targeted interventions during high-risk pregnancies, aiming to improve maternal and children's health. Because the development of new therapeutic approaches to treat pregnancy complications is severely restricted, pilot data are likely continue to emerge from observations on pregnancy outcomes in female patients treated with therapies that target B cells, such as rituximab, a monoclonal antibody directed against the B cell surface antigen CD20 [24].
