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.

Author information

Author notes

    • Azure N Faucette

    Present address: Department of Biology, City University of New York Kingsborough Community College, Brooklyn, New York, USA.

    • Bihui Huang
    •  & Azure N Faucette

    These authors contributed equally to this work.

Affiliations

  1. Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan, USA.

    • Bihui Huang
    • , Azure N Faucette
    • , Michael D Pawlitz
    • , Bo Pei
    • , Joshua W Goyert
    • , Jordan Zheng Zhou
    • , Nadim G El-Hage
    • , Jason Lin
    • , Fayi Yao
    • , Robert S Dewar III
    • , Japnam S Jassal
    • , Jing Dai
    • , Ronald A Nichols
    • , Theodore B Jones
    • , Karoline S Puder
    • , Bernard Gonik
    • , Nihar R Nayak
    • , Elizabeth Puscheck
    •  & Kang Chen
  2. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA.

    • Jie Deng
  3. Leadership in Medicine Program, Union College, Schenectady, New York, USA.

    • Maxwell L Sandberg
  4. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Montserrat Cols
    •  & Cong Shen
  5. Department of Oncology, Wayne State University, Detroit, Michigan, USA.

    • Lisa A Polin
    • , Wei-Zen Wei
    •  & Kang Chen
  6. Department of Obstetrics and Gynecology-Med Ed, Beaumont Dearborn Hospital, Dearborn, Michigan, USA.

    • Ronald A Nichols
    •  & Theodore B Jones
  7. Department of Pathology, Wayne State University, Detroit, Michigan, USA.

    • Martin H Bluth
  8. Catalan Institute for Research and Advanced Studies, Barcelona Biomedical Research Park, Barcelona, Spain.

    • Andrea Cerutti
  9. Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.

    • Andrea Cerutti
  10. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Andrea Cerutti
  11. Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Andrea Cerutti
    • , Marco Colonna
    •  & Kang Chen
  12. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Marco Colonna

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kang Chen.

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DOI

https://doi.org/10.1038/nm.4244

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