Many researchers in the academic and clinical communities theorise that inflammation may underpin the placental dysfunction to which the majority of fetal growth restriction (FGR) and stillbirth cases are attributed. Villitis of unknown etiology (VUE) is an inflammatory condition of the placenta characterised by lesions of macrophages and T cells in the villous stroma. This study addressed the hypothesis that VUE is a maternal-mediated immune reaction that contributes to FGR and stillbirth by detrimentally affecting placental function. The hypothesis was tested by: 1) completing a systematic review of the literature to confirm implied links of VUE to poor pregnancy outcome, 2) performing a detailed characterisation of the cellular phenotype of VUE in stillbirth, 3) developing an in vitro model of VUE and 4) examining the functional effects of VUE using this model. A systematic review of the literature revealed that VUE occurred in 28.6% of placentas from FGR pregnancies compared to 15.6% of placentas from appropriately grown infants (p < 0.0001), confirming the implied association. There were insufficient published studies to be able to corroborate a link with stillbirth. Elevated numbers of macrophages, CD4 and CD8 T cells were quantified in VUE lesions. There were significant increases in pan-placental CD4 and CD8 T cell presence in placentas from stillborn infants with VUE (p < 0.0001). A greater staining area of pro-inflammatory cytokines interleukin (IL)-2 (p < 0.05) and IL-12 (p < 0.0001) was recorded in VUE lesions and a reduction in the anti-inflammatory cytokine IL-4 in the stillbirth with VUE cohort. Dual immunofluorescence of cell markers and cytokines implies that the immune response in VUE is directed towards Th1-type cell-mediated immunity. An in vitro model of VUE was developed that enabled co-culture of explants with fluorescently labelled T cells isolated from matched maternal whole blood samples. Placental tissue and T cells could be maintained in culture for the required duration of the experiment and placental function was not affected by preparation and culture conditions. In vitro co-culture with maternal T cells resulted in a significant reduction in placental function as measured by hCG secretion (p=0.015). There were significant increases in culture supernatant concentrations of IL-1β (p=0.008), IL-10 (p=0.02), interferon-γ (p=0.02) and IL-1Ra (p=0.05) and tissue lysate concentrations of IL-6 (p=0.008) and IL-1β (p=0.02). Culture of explants with a combination of IL-2, IL-12 and anti-IL-4 significantly reduced hCG secretion compared to control (p=0.03).These studies indicate that VUE involves a Th1-type immune response that may affect placental function, the impact of which might be impaired fetal growth that could contribute to stillbirth. The novel in vitro model facilitates future investigations into the pathophysiology of VUE.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677832 |
| Date | January 2016 |
| Creators | Derricott, Hayley |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/villitis-of-unknown-etiology-vue-unravelling-placental-dysfunction-and-causes-of-stillbirth-and-fetal-growth-restriction(1ae67afa-e02d-4b3e-b679-69fb7124fd53).html |
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