Editors' ChoiceReproductive Biology

B cells prevent preterm labor

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Science Signaling  17 Jan 2017:
Vol. 10, Issue 462, eaam7592
DOI: 10.1126/scisignal.aam7592

Premature labor and consequent neonatal mortality may be prevented by stimulating the expression of PIBF1 in uterine B cells.

Systemic infection and inflammation can cause premature (“preterm”) labor before 37 weeks of gestation, and preterm birth is a leading cause of neonatal mortality worldwide. B cells combat infection and suppress inflammation by producing antibodies and interleukin-10 (IL-10), respectively, and maternal B cells are substantially modified during pregnancy, presumably to avoid rejection of the semi-allogeneic fetus. B cell dysfunction is associated with pregnancy complications, including preterm labor. Huang et al. isolated and characterized B cells from the choriodecidual stroma (a part of the uterine lining) obtained from women undergoing term or preterm labor. Preterm samples had a greater number and activation of B cells and supposed “B-1” cells, which can secrete auto- and polyreactive immunoglobulin, and preterm choriodecidual epithelial/stromal tissue was enriched in several B cell–stimulating molecules. However, in a mouse model of systemic inflammation–induced preterm labor using lipopolysaccharide (LPS) as the inflammatory stimulus, B cell deficiency promoted uterine inflammation and a higher incidence of preterm labor and neonatal mortality, indicating that B cells protected against preterm labor. The hormone progesterone promotes full-term pregnancy, and isoforms of the immunomodulatory protein progesterone-induced blocking factor 1 (PIBF1) are secreted by immune cells and trophoblasts during pregnancy. Various immunoassays revealed that human choriodecidual B cells are abundant in PIBF1 during late gestation. B cell–deficient mice had lower basal and LPS-induced expression of Pibf1 in late gestation uterine tissue but similar serum progesterone concentrations when compared with wild-type mice. LPS-induced Pibf1 expression was restored through adoptive B cell transfer, and administration of recombinant full-length (but not a C-terminal fragment of) human PIBF1 to B cell–deficient mice decreased LPS-induced uterine inflammation and preterm labor and delivery and neonatal mortality. A cytokine screen in human peripheral B cells revealed that IL33 promoted PIBF1 expression; uterine B cells from Il33−/− mice at late gestation had decreased expression of Pibf1. IL-33 is a “danger signal” indicating tissue damage; however, preterm human choriodecidual B cells had reduced abundance of both the IL-33 receptor α-chain and PIBF1, indicating that despite being greater in number and activation, diminished reception of the IL-33 danger signal and thus reduced induction of PIBF1 prevents B cells from mounting a protective response to inflammation during late pregnancy. The study reveals new therapeutic avenues to explore for patients at risk of premature labor.

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