Abstract
Preterm birth (PTB) is a leading cause of neonatal death worldwide1. Intrauterine and systemic infection and inflammation cause 30–40% of spontaneous preterm labor (PTL)2, which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL3,4, the functions of B cells in pregnancy are not well known5,6,7,8. We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell–deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell–deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the α-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL.
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Acknowledgements
We thank the European Conditional Mouse Mutagenesis Program and Barry Rosen (Wellcome Trust Sanger Institute) for mouse Il33 targeting vectors, the NIAID Mucosal Immunology Studies Team (MIST) mouse core for generating the Il33−/− lacZ reporter mice, and M. Treadwell (University of Michigan at Ann Arbor) and X. Xu (Bristol-Myers Squibb) for discussion of the manuscript. This study was supported by grants from the Burroughs Wellcome Fund (Preterm Birth Initiative), US National Institutes of Health (U01AI95776 MIST Young Investigator Award, R21AI122256, P30CA22453), American Congress of Obstetricians and Gynecologists and Wayne State University (Perinatal Initiative) (to K.C.). A.N.F. was partially supported by a fellowship from the Wayne State University Office of the Vice President for Research.
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B.H. designed and performed the research, discussed and analyzed the data, and wrote the paper. A.N.F. designed and performed the research and analyzed the data. M.D.P., B.P., J.W.G., J.Z.Z., N.G.E.-H., J. Deng, J.L., F.Y., R.S.D., J.S.J., M.L.S., J. Dai, M.C., C.S. and L.A.P. performed the research and analyzed the data. R.A.N., T.B.J., M.H.B. and K.S.P. provided specimens. B.G., N.R.N., E.P. and W.-Z.W. revised the manuscript. A.C. and M.C. discussed the data. K.C. conceived the study, supervised and performed the research, discussed and analyzed the data, and wrote the paper.
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Huang, B., Faucette, A., Pawlitz, M. et al. Interleukin-33-induced expression of PIBF1 by decidual B cells protects against preterm labor. Nat Med 23, 128–135 (2017). https://doi.org/10.1038/nm.4244
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DOI: https://doi.org/10.1038/nm.4244
