Regulatory B Cells Are Decreased and Impaired in Their Function in Peripheral Maternal Blood in Pre-term Birth

Abstract

Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation. The causes of PTB are multiple and complex, the underlying pathophysiology being largely unknown. Interferences in the fine-tuned balance of the maternal immune system have been pointed to as one possible cause of PTB. Regulatory B cells (Breg) are part of the adaptive immune response, and recent data suggest that they may contribute to a healthy pregnancy by their regulatory/suppressive function. We investigated the frequency of Breg cells in peripheral blood of women undergoing PTB and control women immediately before giving birth via cesarean section. We detected an enhanced number of B cells, but a reduced number of Breg cells in women delivering preterm. In addition, the percentage of IL-10-producing B cells was decreased in PTB following stimulation with TLR agonists CpG or LPS, alone or combined with CD40L. This was associated with increased levels of pro-inflammatory cytokines in maternal serum. Moreover, isolated maternal B cells before delivering premature babies secreted higher level of the pro-inflammatory cytokine IL-6. No alterations in the frequency of regulatory T cells were found. Our data indicate that alterations in the number and function of Breg cells in peripheral maternal blood contribute to the immunological changes observed in preterm delivery and suggest these cells as important regulators of maternal immune responses.

Maternal B Cell-Intrinsic MyD88 Signaling Mediates LPS-Driven Intrauterine Fetal Death

“…We also observed B10 expansion during pregnancy in mice and humans [7][8][9]: here, IL-10 helps to hamper the proinflammatory cytokines produced by maternal T cells [8]. The inability to expand this population is associated with fetal rejection in mice [7] and spontaneous abortion or preterm delivery in humans [8,9]. As such, transferring B10 cells or a subpopulation of B1a B cells characterized by high PC1 expression and IL-10 secretion can normalize the otherwise increased spontaneous abortion rate in an experimental mouse model [10].…”

“…Consequently, our follow-up study aimed to understand the signaling mechanisms activated by LPS in maternal B cells and the role in pregnancy complications, particularly in IUFD. We also observed B10 expansion during pregnancy in mice and humans [7][8][9]: here, IL-10 helps to hamper the proinflammatory cytokines produced by maternal T cells [8]. The inability to expand this population is associated with fetal rejection in mice [7] and spontaneous abortion or preterm delivery in humans [8,9].…”

IL-10 Producing B Cells Protect against LPS-Induced Murine Preterm Birth by Promoting PD1- and ICOS-Expressing T Cells

“…Increased RANTES and MCP-1 levels were also detected in the serum from CD19 −/− and µMT mice. We previously observed enhanced inflammatory cytokine concentrations in human PTB [ 4 , 5 , 30 ]. Others found this connection also in murine PTB models [ 31 , 32 ].…”

“…A reduced number of ICOS-expressing peripheral T cells were determined in patients with spontaneous preterm labor, preeclampsia and HELLP syndrome [ 67 , 68 ]. Since we have shown that patients with spontaneous preterm labor, preeclampsia or HELLP syndrome had elevated levels of pro-inflammatory cytokines such as IL-6 and a diminished percentage of IL-10-secreting B cells [ 4 , 5 , 30 ], ICOS-expressing T cells may be involved in the regulation of IL-10-secreting B cells.…”

“…We have recently introduced B cells as central players in human pregnancy and of relevance for PTB [ 4 , 5 ]. B cells are mostly known as mediators of humoral immune responses since they are able to secrete antibodies following activation and differentiation.…”