Developmental regulation of Th17‐cell capacity in human neonates

Black, Allison; Bhaumik, Suniti; Kirkman, Richard; Weaver, Casey T.; Randolph, David A.

doi:10.1002/eji.201141847

Cited by 70 publications

(52 citation statements)

References 43 publications

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“…88 According to our results, AD and control adults had higher IL-17 only among CLA − subsets compared to their respective pediatric counterparts. This may be due to a selectively higher IL-17 signal in CLA + cells in children, but the trend of lower Th17 in AD children compared to controls suggests that AD children are failing to properly build this axis within the cutaneous compartment.…”

Section: Discussionsupporting

confidence: 55%

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Czarnowicki

Esaki

Gonzalez

et al. 2015

Journal of Allergy and Clinical Immunology

192

171

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Background Identifying differences and similarities between CLA+ polarized T-cell subsets in pediatric vs. adult atopic dermatitis (AD) is critical for directing new treatments towards children. Objective To compare activation markers and frequencies of skin-homing (CLA+) vs. systemic (CLA−) “polar” CD4 and CD8 T-cell subsets in early pediatric AD, adult AD and controls. Methods Flow cytometry was used to measure CD69/ICOS/HLA-DR frequency in memory subsets as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children <5 years and 42 adults with well-characterized moderate to severe AD, as well as age-matched controls (17 children and 25 adults). Results Selective ICOS activation (P<0.001) was seen in children. CLA+ Th2 T-cells were markedly expanded in both AD children and adults compared to controls, but decreases in CLA+ Th1 T-cells were greater in AD children (17% vs. 7.4%, P=0.007). Unlike in adults, no imbalances were detected in pediatric AD CLA− T-cells, nor were there altered frequencies of Th22 T-cells within CLA+ or CLA− compartments. Adults with AD had increased frequency of IL-22-producing CD4 and CD8 T-cells within the skin-homing population (9.5% vs. 4.5%; 8.6% vs. 2.4%, respectively; P<0.001) as well as increased HLA-DR activation (P<0.01). Conclusions These data suggest that Th2 activation within skin-homing T-cells may drive AD in children and that reduced counter-regulation by Th1 T-cells may contribute to excess Th2 activation. Th22 “spreading” of AD is not seen in young children and may be influenced by immune development, disease chronicity or recurrent skin infections. Clinical Implications Therapeutic approaches to treat AD in children may be best directed to correction of Th2/Th1 imbalance, while adults might also benefit from IL-22 targeted therapies.

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Section: Discussionsupporting

confidence: 55%

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Czarnowicki

Esaki

Gonzalez

et al. 2015

Journal of Allergy and Clinical Immunology

192

171

View full text Add to dashboard Cite

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“…The greater developmental "plasticity" of neonatal lymphocytes and a Th17 bias could facilitate the conversion of Tregs and/or the differentiation of naive CD4 cells toward proinflammatory phenotypes (22,23), an effect that could be particularly enhanced in an inflammatory context …”

Section: Discussionmentioning

confidence: 99%

Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model

et al. 2014

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Background: Chorioamnionitis, an inflammatory gestational disorder, commonly precedes preterm delivery. Preterm infants may be at particular risk for inflammation-related morbidity related to infection, although the pathogenic mechanisms are unclear. We hypothesized that maternal inflammation modulates immune programming to drive postnatal inflammatory processes. Methods: We used a novel combined murine model to treat late gestation dams with low-dose lipopolysaccharide (LPS) and to secondarily challenge exposed neonates or weanlings with Sendai virus (SeV) lung infection. Multiple organs were analyzed to characterize age-specific postnatal immune and inflammatory responses. results: Maternal LPS treatment enhanced innate immune populations in the lungs, livers, and/or spleens of exposed neonates or weanlings. Secondary lung SeV infection variably affected neutrophil, macrophage, and dendritic cell proportions in multiple organs of exposed pups. Neonatal lung infection induced brain interleukin (IL)-4 expression, although this response was muted in LPS-exposed pups. Adaptive immune cells, including lung, lymph node, and thymic lymphocytes and lung CD4 cells expressing FoxP3, interferon (IFN)-γ, or IL-17, were variably prominent in LPS-exposed pups. conclusion: Maternal inflammation modifies postnatal immunity and augments systemic inflammatory responses to viral lung infection in an age-specific manner. We speculate that inflammatory modulation of the developing immune system contributes to chronic morbidity and mortality in preterm infants. c horioamnionitis, an antenatal inflammatory disorder, is detected in the majority of placentas following extremely preterm delivery (1). The resultant fetal inflammation has been associated with postnatal development of chronic inflammatory disorders, including retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis (2-4). However, the pathogenic role of chorioamnionitis in neonatal morbidity, particularly regarding

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“…Neonates have an enhanced ability to mount proinflammatory T H 17 responses, based on research showing that TLR-stimulated cord blood cells produce high levels of IL-6 and IL-23, necessary cytokines for T H 17 differentiation 29 . In addition, cultured cord blood CD4 + T cells can generate significant amounts of IL-17 30 . In the neonatal setting of a fully mature T H 17 pathway, is it possible that an aggressive, persistent T H 17 response plays a role in bile duct damage in BA?…”

Section: Adaptive Cellular Immunity: T-cell Subsetsmentioning

confidence: 99%

What Causes Biliary Atresia? Unique Aspects of the Neonatal Immune System Provide Clues to Disease Pathogenesis

Mack

2015

Cellular and Molecular Gastroenterology and Hepatology

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Biliary atresia (BA) is the most frequent identifiable cause of neonatal cholestasis, and the majority of patients will need liver transplantation for survival. Despite surgical intervention with the Kasai portoenterostomy, significant fibrosis and cirrhosis develop early in life. An increased understanding of what causes this inflammatory fibrosing cholangiopathy will lead to therapies aimed at protecting the intrahepatic biliary system from immune-mediated damage. This review focuses on studies pertaining to the role of the adaptive immune response in bile duct injury in BA, including cellular and humoral immunity. The neonatal presentation of BA prompts the question of what potential modifications of unique aspects of the neonatal immune system set the stage for the progressive biliary disease. This review also discusses the characteristics of neonatal immune response and the theories on how alterations of this response could contribute to the pathogenesis of BA. These include aberrant type 1 helper T-cell (TH1) and TH17 responses, deficiencies in regulatory T cells, activation of humoral immunity, and autoimmunity. To advance our understanding of the etiology of BA, future studies should focus on the unique aspects of the neonatal immune system that have gone awry.

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Developmental regulation of Th17‐cell capacity in human neonates

Cited by 70 publications

References 43 publications

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model

What Causes Biliary Atresia? Unique Aspects of the Neonatal Immune System Provide Clues to Disease Pathogenesis

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