**1. Introduction**

Preeclampsia (PE) is a placental disorder affecting 2–8% of pregnancies with the highest burden observed in poor countries [1–4]. PE and severe PE are characterized by exacerbated pro-inflammatory (PI) responses, leading to significant maternal and perinatal morbidity and mortality [5–8]. Successful placentation and the subsequent fetal development depend on the delicate balance between moderate PI response and immune tolerance.

Recent data has shown that the B cell profile is changed during pregnancy to accommodate the growing fetus [9, 10]. Findings have pointed out a crucial role for regulatory B cells (Bregs) in establishing an immunomodulatory (IM) environment relevant for pregnancy [11]. In a steady state, Bregs represent 10% of B cells in peripheral blood, a proportion which increases during pregnancy, with the highest rate being observed in post-partum [12, 13]. Studies have demonstrated an IM function for IL-10-producing Bregs against ongoing inflammatory events to both limits the infection [14] and promote a successful outcome of pregnancy [15, 16]. It was also shown that early transfer of Bregs from normal pregnant to abortion-prone mice prevented fetal rejection and restored pregnancy tolerance [17].

Indeed, the maternal immune system needs to recognize and accommodate a developing semi-allogeneic fetus. Regulatory T cells are shown to contribute to normal pregnancy, and considering the immune regulatory involvement of Bregs cells in the fields of autoimmunity, transplantation tolerance, and cancer biology, the mechanism underlying Bregs activities during pregnancy needs to be unraveled [18–20]. The immune regulatory function of Bregs consist of inhibition of the differentiation of effector T cells and dendritic cells (DCs), and activation of Tregs [21, 22].

Today, the consensus is not fully established on the characterization of Bregs with respect to cell surface markers. Recent studies have shown that the regulative roles of Bregs are due to the production of the antiinflammatory cytokine interleukin-10 (IL-10) [23–25]. However, recent data indicated that some B cell subsets perform regulatory functions without IL-10 involvement suggesting that other Bregs use multimechanistic to regulate immune responses.

In mice, multiple B cell subsets are identified to play regulatory function and include the marginal-zone B cells, the transitional 2 marginal-zone precursor cells, follicular B cells, CD5+ CD178+ killer B cells, plasma cells, plasmablasts, CD5+ CD1dhiIL-10+ B cells, CD5+ B-1a cells, GIFT-15 B cells, TIM-1+ B cells, and PD-L1hi B cells [26, 27]. The IL-10-producing Bregs, also called B10 cells have the CD1dhiCD5+ phenotype [28].

In humans, immature B cells, IL-10<sup>+</sup> B cells (B10), GrB<sup>+</sup> B cells, Br1 cells, and plasmablasts are identified to have immunosuppressive functions [26]. Previous data in humans have described Bregs as CD19+ CD24hiCD27+ [29], which are analogous to the mouse B10 cells [26] and CD19<sup>+</sup> CD24hiCD38hi cells [26] with the ability to produce IL-10 and to express CD80 and CD86 costimulation molecules [30].

This disparity of these regulatory cells suggests that Bregs are not derived from one specific lineage; rather they may become Bregs following exposure to environmental stimuli such as placenta derived-exosomes.

As PE is PI disease and syncytiotrophoblast (STB)-derived exosomes (SDE) contribute to materno-foetal immuno-tolerance, it will be relevant to understand how STB cells and SDE contribute to PE by altering Bregs differentiation and function during human pregnancy. We will discuss whether a disrupted balance of Bregs could increase susceptibility to PE.
