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Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus

Jackson, Courtney M
http://orcid.org/0000-0002-1777-688X
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592818915104982

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Immunology.
A complication that can occur during pregnancy is placenta inflammation, referred to as chorioamnionitis (chorio). Exposure to this inflammatory condition has been associated with several post-natal morbidities. Chorio, particularly severe chorio leads to the increased production of various inflammatory mediators in the amniotic fluid. This inflamed amniotic fluid encounters the fetus, resulting in systemic and mucosal immune responses. However, a full understanding of the fetal responses to the inflammatory milieu created by chorio and the contribution of inflammatory cytokines like IL-1 and TNFa to these responses remains limited. The work presented here examined and characterized the fetal systemic and mucosal immune response to chorio exposure in humans and in a non-human primate (NHP) animal model. Our NHP model in which using intra-amniotic (IA) LPS in the Rhesus macaque, phenocopies severe chorio and allowed us to evaluate the impact of chorio exposure on the fetus. Systemically we found that IA LPS leads to a decreased frequency of CD4+FoxP3+ regulatory T cells (Tregs). However, while CD4+FoxP3+ Tregs are reduced in the context of chorio, they markedly upregulate production of IL-17, becoming the most significant source of this cytokine in inflammatory conditions. A similar, but milder phenotype was found in the cord blood as well. We later found that the Th17-like response was partially controlled by IL-1 or TNFa signaling, but the frequency of CD4+FoxP3+ did not recover after blockade IL-1 or TNF. The presence of a chorio induced Th17-like signature was also found in human cord blood of severe chorio exposed fetuses with sustained elevation of RORC and RORC/FOXP3 mRNA ratio. These findings point to a regulatory/inflammatory disbalance in the fetal systemic response to chorio exposure that particularly impacts regulatory T cells. In our NHP Rhesus macaque model, we also conducted an in-depth analysis of the chorio-induced fetal mucosal immune response in the lung and intestine. IA LPS induced acute fetal lung inflammation characterized by the infiltration of myeloid cells and elevated inflammatory mediators, a phenotype albeit absent in the intestine. Single cell RNAseq analysis revealed the presence of highly active and responsive infiltrating myeloid cells (monocytes/macrophages and neutrophils) in the fetal lung. Multi-parameter flow cytometry confirmed their presence in addition to activated dendritic cells, while there was no major difference in B and T lymphocytes, including regulatory T cells. Treatment of LPS-exposed animals with anti-TNF and IL-1RA partially blunted the myeloid cell infiltration, while anti-TNF was more efficient than IL-1RA at diminishing cytokine expression, even diminishing IL-1ß production. Combined blocking of IL-1 and TNFa did not enhance the effect of the single blockades. Combining observations made in humans with the utility of the Rhesus animal model, our studies provides a unique look into the fetal immune system and its response to in utero inflammatory exposure. While also providing an opportunity to explore potential therapeutic strategies in the amelioration of fetal inflammation. Overall, setting up nicely for continued research in this field.
Claire Chougnet, Ph.D. (Committee Chair)
David Hildeman, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
Alan Jobe, M.D. (Committee Member)
Ian Lewkowich, Ph.D. (Committee Member)
333 p.
Immunology
chorioamnionitis; fetal IL-17 response; immune ontogeny; fetal immune response; fetal immunity; fetal mucosal immunity

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Citations

  • Jackson, C. M. (2020). Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592818915104982

    APA Style (7th edition)

  • Jackson, Courtney. Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592818915104982.

    MLA Style (8th edition)

  • Jackson, Courtney. "Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592818915104982

    Chicago Manual of Style (17th edition)

ucin1592818915104982
294
© 2020, some rights reserved.Creative Commons License Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus by Courtney M Jackson is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.
Release 3.2.12