Functions of B cells in pregnancy

The functions of B cells in pregnancy are poorly understood; indeed, these cells have been considered to be rare or absent in the decidua. Reporting in Nature Medicine, Huang et al. describe a previously unappreciated role for B cells in protecting against pre-term labour (PTL) by producing progesterone-induced-blocking factor 1 (PIBF1).

Pre-term birth is a leading cause of neonatal death and morbidity. In most cases, pre-term birth is preceded by spontaneous PTL, which can arise owing to infection or inflammation. The immune mechanisms involved in PTL and pre-term birth are not well understood, and the authors set out to explore a potential role for B cells. They assessed samples of choriodecidua from women who had undergone spontaneous term labour (TL) or PTL and found that B cells were present and accounted for approximately 1% and 2.5% of CD45+ cells, respectively, in each group. As well as containing higher overall numbers of B cells, the choriodecidua of the PTL subjects contained higher numbers of cells with a B1 cell phenotype and more plasma cells. The expression of various B cell-stimulating factors was also higher in the choriodecidua of the PTL subjects, but interleukin-10 (IL-10) expression was lower.

The authors next used animal models to assess whether B cells protect against inflammation-triggered PTL. In a model of PTL induced by systemic lipopolysaccharide (LPS) challenge on gestational day 16.5, wild-type mice were relatively resistant to pre-term delivery and showed low fetal mortality. By contrast, B cell-deficient μMT mice experienced high rates of PTL and fetal mortality; this was associated with uterine induction of proinflammatory cytokines and neutrophil infiltration. The transfer of either wild-type or IL-10-deficient B cells protected μMT mice against PTL and fetal mortality, suggesting that B cells mediate protection independently of IL-10.

As progesterone is important in the maintenance of term pregnancy, the authors examined whether B cell deficiency affects progesterone responses. Indeed, they found that in late gestation, pregnant μMT mice had lower uterine levels of PIBF1, which is responsible for many of the effector functions of progesterone during pregnancy. Furthermore, pregnant μMT mice showed defective uterine induction of Pibf1 following LPS challenge, despite having normal serum levels of progesterone. Transfer of B cells to pregnant μMT mice resulted in higher uterine induction of Pibf1, and further analyses showed that mouse uterine B cells produce PIBF1 during mid and late gestation. Human choriodecidual B cells were also found to express PIBF1 during late gestation, and administration of human PIBF1 to μMT mice significantly reduced PTL and fetal mortality following LPS challenge.

The authors showed that, in a similar manner to progesterone, the tissue alarmin IL-33 induces PIBF1 expression in human peripheral and choriodecidual B cells. IL-33-deficient mice showed decreased uterine expression of PIBF1 in late gestation, whereas progesterone withdrawal in late pregnancy was not associated with decreased uterine PIBF1 levels. Therefore, IL-33, rather than progesterone, seems to maintain PIBF1 expression in late gestation. The authors found that choriodecidual B cells from PTL subjects expressed lower levels of IL-33 receptor α-chain (also known as ST2) and PIBF1 compared with choriodecidual B cells from TL subjects. PIBF1 expression was also lower in the choriodecidua of PTL subjects, despite these individuals showing similar progesterone levels to TL subjects. These data indicate that uterine B cells may protect against PTL by producing PIBF1. The authors suggest that therapies targeting the IL-33 and PIBF1 signalling pathways could be developed for the prevention and treatment of human PTL.

Reference: Huang, B. et al. Interleukin- 33-induced expression of PIBF1 by decidual B cells protects against preterm labour. Nat. Med. http://dx.doi.org/10.1038/nm.4244 (2016).

FURTHER READING Liew F.Y., Girard J.P. & Turnquist H. R. Interleukin-33 in health and disease. Nat. Rev. Immunol. 16, 676–689 (2016)

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