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

Anne Marie Singh, Michael G. Sherenian, Kwang-Youn A Kim, Kristin A. Erickson, Amy Yang, Karen K L Mestan, Linda M. Ernst, Rajesh Kumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background: Chorioamnionitis 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. Methods: We 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. 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.

Original languageEnglish (US)
Article number66
JournalAllergy, Asthma and Clinical Immunology
Volume14
Issue number1
DOIs
StatePublished - Nov 19 2018

Fingerprint

Chorioamnionitis
Fetal Blood
Fetus
Inflammation
Live Birth
Regulatory T-Lymphocytes
Nonparametric Statistics
Lung
Linear Models
Asthma
Phenotype
Tretinoin
Thymus Gland
Placenta
B-Lymphocytes

Keywords

  • Asthma
  • Chorioamnionitis
  • Foxp3
  • Pediatrics
  • RORγt
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pulmonary and Respiratory Medicine

Cite this

@article{29aed0ce7e634c1b875f5f186f2b9eb7,
title = "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 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. Methods: We 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. 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.",
keywords = "Asthma, Chorioamnionitis, Foxp3, Pediatrics, RORγt, T cells",
author = "Singh, {Anne Marie} and Sherenian, {Michael G.} and Kim, {Kwang-Youn A} and Erickson, {Kristin A.} and Amy Yang and Mestan, {Karen K L} and Ernst, {Linda M.} and Rajesh Kumar",
year = "2018",
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Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis. / Singh, Anne Marie; Sherenian, Michael G.; Kim, Kwang-Youn A; Erickson, Kristin A.; Yang, Amy; Mestan, Karen K L; Ernst, Linda M.; Kumar, Rajesh.

In: Allergy, Asthma and Clinical Immunology, Vol. 14, No. 1, 66, 19.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis

AU - Singh, Anne Marie

AU - Sherenian, Michael G.

AU - Kim, Kwang-Youn A

AU - Erickson, Kristin A.

AU - Yang, Amy

AU - Mestan, Karen K L

AU - Ernst, Linda M.

AU - Kumar, Rajesh

PY - 2018/11/19

Y1 - 2018/11/19

N2 - Background: Chorioamnionitis 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. Methods: We 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. 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.

AB - Background: Chorioamnionitis 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. Methods: We 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. 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.

KW - Asthma

KW - Chorioamnionitis

KW - Foxp3

KW - Pediatrics

KW - RORγt

KW - T cells

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DO - 10.1186/s13223-018-0297-y

M3 - Article

VL - 14

JO - Allergy, Asthma and Clinical Immunology

JF - Allergy, Asthma and Clinical Immunology

SN - 1710-1484

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