BackgroundHistologic chorioamnionitis (HCA) is a placental inflammatory disorder that frequently precedes preterm delivery. HCA increases risk for long-standing inflammatory injury and may influence immune programming, particularly in preterm (PT) neonates. We hypothesized that HCA exposure is associated with an increased circulating frequency of pro-inflammatory, Th17-type responses.MethodsPlacental cord blood was collected from HCA-exposed or control neonates (23-41 weeks gestation). Frequencies of Th17 and T regulatory (Treg) cells and assessments of Th17-type features in CD4 and Treg cells were determined by flow cytometric analysis.ResultsCord blood samples from 31 PT and 17 term neonates were analyzed by flow cytometry. A diagnosis of HCA in extremely PT (EPT, GA ≤ 30 wk) gestations was associated with the highest cord blood frequencies of progenitor (pTh17, CD4+CD161+) and mature (mTh17, CD4+CD161+CCR6+) Th17 cells. Preterm neonates exposed to HCA also exhibited elevated cord blood frequencies of IL-17+ Treg cells, as well as T cells with effector memory phenotype (TEM) that co-expressed Th17-type surface antigens.ConclusionTh17-type responses are amplified in preterm neonates exposed to HCA. We speculate that a Th17 bias may potentiate the inflammatory responses and related morbidity observed in preterm neonates whose immune systems have been ‘primed’ by HCA exposure.
Background Group B Streptococcus (GBS) infection causes inflammatory co-morbidities in newborns. While the mechanisms remain unclear, evidence suggests that impaired innate-adaptive immune interactions may be contributory. We hypothesized that GBS-stimulated neonatal neutrophils provide a milieu that may drive pro-inflammatory T helper cell programming. Methods Neutrophils were stimulated with Type III GBS (COH1); supernatants or intact neutrophils were co-cultured with CD4+ T cells or Treg cells. Resulting intracellular cytokines and nuclear transcription factors were determined by multicolor flow cytometry. Results GBS-stimulated neutrophils released soluble mediators that induced greater IL-17 responses in neonatal vs. adult CD4+ T cells in the absence of added polarizing cytokines. GBS-stimulated neonatal neutrophils also induced robust expression of the canonical nuclear transcription factors for Th1 (Tbet) and Th17 (IL-17) cells in CD4+ T cells. Following GBS stimulation, both intact neutrophils and neutrophil-derived mediators promoted the generation of Tregs with Th1 and Th17 characteristics. Conclusion GBS-stimulated neonatal neutrophils bias the in vitro Th differentiation program of neonatal CD4+ T cells and promote pro-inflammatory Th1 and Th17 phenotypes in Tregs. Our data suggest that developmental modifications of innate-adaptive immune cross-talk mechanisms may contribute to the inflammatory complications associated with neonatal GBS infection.
Introduction: Maternal–fetal immune crosstalk mechanisms are increasingly identified in the pathogenesis of gestational disorders, including histologic chorioamnionitis (HCA). Although an inflammatory Th17 immune phenotype has been described in preterm neonates with HCA, the associated maternal Th17 response is relatively unknown. To refine our understanding of Th17 biology in this context, we examined Th17 responses in maternal-cord blood dyads of preterm gestations. Materials and methods: Paired maternal and cord blood (CB) samples were prospectively collected from preterm gestations (23–34 weeks) with HCA or controls. Th17-linked cell frequencies and plasma calgranulin (S100A8, S100A12) levels were determined by flow cytometry and enzyme-linked immunoassay, respectively. Results: Analyses of 47 maternal-cord blood pairs showed striking parallel increases in Th17 cell frequencies as well as plasma calgranulin levels in the presence of fetal inflammation. Cord blood S100A12 levels were directly correlated with Th17 cell frequencies. In CB cultures, rh-S100A12 promoted in vitro propagation of Th17-type CD4 + cells. Conclusions: Maternal and CB Th17-linked responses are dually amplified in gestations with HCA, supporting a biological role for maternal–fetal interactions in this disorder. In addition to advancing current knowledge of neonatal Th17 mechanisms, these data shed new light on their association with maternal inflammation.
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