Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis

Abstract

Background

Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased T_H17-to-T_reg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known.

Methods

We enrolled two cohorts to evaluate T_H17 and regulatory T cell (T_reg) 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 T_reg 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.

Results

In 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.

Conclusion

Exposure 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.

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