Linked Th17 and Calgranulin Responses in Maternal-cord Blood Dyads of Preterm Gestations with Histologic Chorioamnionitis.

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.

Neonatal neutrophils stimulated by group B Streptococcus induce a proinflammatory T-helper cell bias.

BackgroundGroup B Streptococcus (GBS) infection causes inflammatory comorbidities 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 proinflammatory T-helper (Th) cell programming.MethodsNeutrophils were stimulated with Type III GBS (COH1); supernatants or intact neutrophils were cocultured with CD4+ T cells or regulatory T cells (Tregs). Resulting intracellular cytokines and nuclear transcription factors were determined by multicolor flow cytometry.ResultsGBS-stimulated neutrophils released soluble mediators that induced greater interleukin-17 (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.ConclusionGBS-stimulated neonatal neutrophils bias the in vitro Th differentiation program of neonatal CD4+ T cells and promote proinflammatory 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.

Augmented Th17-type immune responses in preterm neonates exposed to histologic chorioamnionitis.

BACKGROUND: Histologic 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 proinflammatory, Th17-type responses. METHODS: Placental cord blood was collected from HCA-exposed or control neonates (23-41 wk 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. RESULTS: Cord 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 coexpressed Th17-type surface antigens. CONCLUSION: Th17-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.

The impact of Meth A fibrosarcoma derived EMAP II on dendritic cell migration.

Studies have suggested that tumors are capable of modulating dendritic cell (DC) phenotype. A soluble protein produced by certain tumors, endothelial monocyte-activating polypeptide II (EMAP II) has been suggested as an anti-tumor agent based on its anti-angiogenic activity. However, this factor has not been evaluated for effects on DC. In this study, we analyzed the effect of Meth A fibrosarcoma supernatant and recombinant human EMAP II on DC migration. This included the migration of Langerhans cells from mouse ear skin sections and the migration of cells of a dendritic cell line (JAWS II) in a transwell culture system. The results of these studies indicated that EMAP II stimulates the migration of DC. Additional studies showed that the presence of the ascites form of the Meth A tumor led to a decrease in Langerhans cell (LC) numbers in the skin, and this decrease could be partially blocked by neutralizing antibody specific for EMAP II. Subcutaneous injection at the base of the ear of recombinant human EMAP II also led to a decrease in epidermal LC similar to that observed in tumor bearing mice. Together, these results suggest novel roles for EMAP II in modulating the migration of DC and suggest that these effects may modify Meth A tumor/host interactions.