Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

Abstract

Maternal immune tolerance toward the fetus is an essential requisite for pregnancy. While T cell functions are well documented, little is known about the participation of B cells. We have previously suggested that IL-10-producing B cells are involved in pregnancy tolerance in mice and humans. By employing murine and human systems, we report now that fetal trophoblasts positively regulate the generation of IL-10-producing B cells. We next studied the participation of hormones produced by the placenta as well as the fetal protein alpha-fetoprotein (AFP) in B cell modulation. Human chorionic gonadotropin (hCG), but not progesterone, estrogen, or a combination of both, was able to promote changes in B cell phenotype and boost their IL-10 production, which was abolished after blocking hCG. The hCG-induced B cell phenotype was not associated with augmented galactosylation, sialylation, or fucosylation of IgG subclasses in their Fc. In vitro, hCG induced the synthesis of asymmetrically glycosylated antibodies in their Fab region. Interestingly, AFP had dual effects depending on the concentration. At concentrations corresponding to maternal serum levels, it did not modify the phenotype or IL-10 secretion of B cells. At fetal concentrations, however, AFP was able to drive B cells into apoptosis, which may indicate a protective mechanism to avoid maternal B cells to reach the fetus. Our data suggest that the fetus secrete factors that promote a pregnancy-friendly B cell phenotype, unraveling interesting aspects of B cell function, and modulation by pregnancy hormones and fetal proteins.

Are B cells altered in the decidua of women with preterm or term labor?

“…B cells were first observed in the placental bed of women early in gestation, which was confirmed by later studies . During early pregnancy, B cells are implicated in the mechanisms of maternal‐fetal tolerance . Decidual B cells modestly increase between 27 and 33 weeks of gestation followed by a slight decline at term .…”

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

“…Prior studies revealed that AFP might play such important roles as pro‐angiogenesis, anti‐oxidation and immunoprotection on the maternal‐fetal interface . But the other study found that the offspring of AFP knockout mice were normal in both pre‐ and post‐natal stages .…”

Immunobiology of Acute Chorioamnionitis

“…Regulatory B cells (Bregs) are the B cells producing IL-10 under the influence of gonadotropins. Bregs are increased in early human pregnancy and suppress TNFα production by T cells (201,202). Maternal Tregs, stimulated by chorionic gonadotrophins, accumulate at the maternal-fetal interface during early gestation (203,204), peak in the second trimester (205), and mediate tolerance to paternal antigens, facilitating embryo implantation and preventing embryo resorption (206)(207)(208)(209).…”

“…Decidual B cells can secrete both pro-inflammatory IL-12 and IL-6, as well as immunosuppressive IL-35 (138) suggesting multiple context-dependent roles for B cells during intrauterine inflammation. Furthermore, CD19 + CD24 hi CD27 + B cells can produce IL-10 under the influence of gonadotropins, and these regulatory B cells (Bregs) are increased in early human pregnancy and suppress TNFα production by T cells (201,202). Additionally, adoptive transfer of IL-10 producing B cells increased the number of uterine Tregs and protected against LPSinduced adverse pregnancy effects by decreasing the production of IL-17A and IL-6 by naïve CD4 + CD25 − T cells (140).…”