Villitis of Unknown Etiology (VUE): Unravelling Placental Dysfunction and Causes of Stillbirth and Fetal Growth Restriction

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Abstract

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.

Layman's Abstract

Stillbirth (the death of a baby before birth) affects 10 families every day in the UK. In 60% of stillbirth cases the placenta, the organ that allows nutrients and oxygen to move from mother to baby, goes wrong. This somehow prevents essential nutrients and oxygen from being transferred to the baby, which can reduce its growth (fetal growth restriction; FGR). If FGR is severe the baby is at a much greater risk of being stillborn.There is a great deal of interest in the role of the mothers’ immune system in pregnancy complications. An increasing body of evidence suggests that inflammation may be important in many cases of FGR and stillbirth. Our study focussed on a condition called villitis of unknown etiology (VUE), which is believed to represent a mother’s immune system recognising the placenta as foreign and rejecting it. VUE is thought to impair placental function which might then go on to cause FGR and/or stillbirth.Previously published studies related to VUE were obtained and analysed. Their results established that VUE is found in significantly more placentas from FGR babies compared to placentas from healthy pregnancies. However, too few studies have been published to enable a definitive link of VUE with stillbirth and this warrants further investigation.This study examined cell types in areas of VUE in the placentas of stillborn infants. The microscopic lesions in the placenta in VUE are made up of specific white blood cells called macrophages, CD4 T cells and CD8 T cells. We also observed, for the first time, evidence that T cells were present in areas of placenta that looked otherwise healthy. The location and amount of the chemical messengers (cytokines) that these cells produce was also altered in stillbirth with VUE.An experiment was devised that allowed growth of fragments of placenta with T cells that had been isolated from mothers’ blood samples. Initial experiments showed that tissue and cells could be prepared without affecting the way that either cell type functioned. Culturing tissue and cells together for a period of 4 days altered the function of the placenta; it produced less of an important hormone called hCG and more cytokines that are known to be associated with inflammation. Culturing tissue with cytokines also caused a decrease in hCG secretion.These studies have shown that the cells and cytokines involved in VUE have the potential to damage the functional ability of the placenta. The new experiments can be used as a basis for further studies into the effect of inflammation on the way this critical organ works.

Keyword(s)

Cytokines; Inflammation; Placenta; Stillbirth; VUE; Villitis

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