Abstract
BackgroundChorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known.MethodsWe enrolled two cohorts to evaluate TH17 and regulatory T cell (Treg) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORγt+) and Treg cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis.ResultsIn the live birth subjects with chronic placental inflammation we observed an increased proportion of RORγt+ cells in Foxp3+ cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORγt+ cells within Foxp3+ cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3+ cells and an increase in lung CD3+ cells compared with subjects that did not have chorioamnionitis.ConclusionExposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORγt+ cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORγt+ cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma.
Highlights
Chorioamnionitis is a risk factor for future asthma development
It has been shown that cord blood levels of interleukin (IL) 1β and IL-6 increase in neonates with chorioamnionitis
Live birth cohort We found a significantly increased proportion of retinoic acidrelated orphan receptor gamma t (RORγt)+ cells within the Forkhead Box P3 (Foxp3)+ cells (CD3+CD4+Foxp3+RORγt+) among individuals with chronic inflammation (β ± SE: 14.19 ± 3.59, p = 0.002; Table 3) when compared to individuals with neither acute or chronic inflammation
Summary
Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known. It is suspected that T reg and T H17 cells may be reciprocally regulated, and IL-17+ like Tregs have been described These IL-17+ Treg cells differentiate to inflammatory TH17 ex vivo, with a loss of FOXP3 expression [14]. The changes in cytokine expression in neonates with chorioamnionitis may eventually promote immune dysregulation, airway remodeling via mucous cell metaplasia, smooth muscle proliferation/migration, and further TH17 activation. In human fetuses, chorioamnionitis is associated with systemic differences in regulatory T cells and TH17 cell number. We sought to determine any tissue specific alterations by evaluating a retrospective cohort of 20 still births of varying gestational age with and without chorioamnionitis
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