Differential gene network analysis for the identification of asthma-associated therapeutic targets in allergen-specific T-helper memory responses

Fifty most significant differentially expressed genes in HDM-stimulated versus resting CD4 T cells from HDM-sensitized atopics with asthmatics. Gene expression patterns were compared between HDM-stimulated and unstimulated CD4 T cells from HDM-sensitized atopics with asthma. Here we present the 50 most significant differentially expressed genes. (XLS 34 kb

Basophil levels in PBMC population during childhood acute wheeze/asthma are associated with future exacerbations

Our data suggest that a basophil level above 0.18% of the PBMC population during an acute respiratory exacerbation is associated with an increased risk for future exacerbations in children with asthma and/or wheeze

Progressive increase of FcεRI expression across several PBMC subsets is associated with atopy and atopic asthma within school-aged children

Background: Antigen-specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non-atopic/non-asthmatic age-matched healthy controls. Methods: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. Results: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non-atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non-asthmatic children also after adjusting for serum IgE levels. Conclusion: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non-asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children

Risk factors for bronchial hyperresponsiveness in teenagers differ with sex and atopic status

Background: Sex-related differences in bronchial hyperresponsiveness (BHR) have been reported in adolescents, but the mechanisms remain obscure

POOR LUNG FUNCTION TRACKS FROM CHILDHOOD TO YOUNG ADULTHOOD, AND IS ASSOCIATED WITH RESPIRATORY SYMPTOMS AND ASTHMA IN 22 YEAR OLD PARTICIPANTS OF THE WESTERN AUSTRALIAN PREGNANCY (RAINE STUDY) COHORT

POOR LUNG FUNCTION TRACKS FROM CHILDHOOD TO YOUNG ADULTHOOD, AND IS ASSOCIATED WITH RESPIRATORY SYMPTOMS AND ASTHMA IN 22 YEAR OLD PARTICIPANTS OF THE WESTERN AUSTRALIAN PREGNANCY (RAINE STUDY) COHOR

Presymptomatic differences in Toll-like receptor function in infants who have allergy

Background: Microbial exposure might play a key role in allergy development, but little is known about the role of Toll-like receptors (TLRs).Objective: This study explored the association between neonatal TLR microbial recognition/function, allergy risk (maternal allergy), and prospective allergy development.Methods: Cord blood mononuclear cells (n = 111) were cultured either alone or with optimal concentrations of TLR ligands: lipoteichoic acid (TLR2), polyinosinicpolycytidylic acid (TLR3), LPS with IFN-? (TLR4), flagellin (TLR5), imiquimod R837 (TLR7), or CpG (TLR9). Cytokine responses were assessed in relation to allergy risk (maternal allergy) and allergy outcomes (sensitization, food allergy, and atopic dermatitis) at 12 months of age.Results: Maternal allergy (n = 59) was associated with significantly higher neonatal IL-12 and IFN-? responses to TLR2, TLR3, and TLR4 activation, whereas TNF-? and IL-6 responses to TLR2, TLR4, and TLR5 activation were significantly higher in newborns who subsequently had allergic disease (n = 32). Notably, consistent with previous reports, newborns who had disease had lower TH1 IFN-? response to mitogens (PHA).Conclusion: Allergic disease was associated with increased (rather than decreased) perinatal TLR responses. Further studies are needed to determine how these responses track in the postnatal period and whether this relative hyperresponsiveness is a product of intrauterine influences, including maternal atopy, functional genetic polymorphisms, or both.<br/

CpG methylation patterns in the IFN gamma promoter in naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics

Interferon-gamma (IFN gamma) gene expression is tightly regulated in early life, and exaggerated negative control of IFN gamma production in CD4(+) T cells has been associated with risk for subsequent development of atopy. Recent studies have demonstrated hypermethylation of CpG sites in the IFN gamma promoter in neonates, a mechanism which in mice leads to strong suppression of IFN gamma gene transcription. In the present study, the methylation status of six CpG sites in the proximal promoter of the human IFN gamma gene was determined by bisulphite sequencing. Cell populations studied were Th1 or Th2 polarized cell lines derived from neonatal and adult CD4(+)/CD45RA(+) T cells, CD4(+) and CD8(+) naive T cells from cord blood of children followed to outcome age 2 for assessment of atopy status, and CD4(+) and CD8(+) naive T cells from 6 yr old and adult atopics and controls. We demonstrate that in vitro differentiation of CD4(+) T cells down the Th1 pathway (but not the Th2 pathway) is accompanied by progressive demethylation of CpG sites in the IFN gamma promoter, which is most marked in neonatal cells. Atopy development by age 2 was not associated with variations in methylation patterns in cord blood T cells. However, IFN gamma promoter methylation was reduced in CD8(+) T cells from atopic children in the age range in which hyperproduction of IFN gamma as recently been identified as a common feature of the atopic phenotype. The findings demonstrate the potency of IFN gamma promoter methylation as a mechanism for control of human IFN gamma gene expression, particularly during early life. Differential regulation of IFN gamma promoter methylation in T cells may be an important contributory factor in atopy development in childhood, and this possibility warrants further detailed investigation

Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development

Virus-associated febrile lower respiratory tract infections (fLRIs) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defense capacity during this period, as exemplified by production of type 1 and 3 interferons (T1/3IFNs), might be an underlying determinant of risk.We sought to investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze.We studied a subset of subjects from a birth cohort at high risk for asthma/allergy and determined the capacity of cord blood cells (n\ua0=\ua0151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic polyinosinic-polycytidylic acid using a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory tract infection history during infancy, wheezing history to 5 age years, and ensuing maturation of innate immune capacity by age 4\ua0years (n\ua0=\ua0160) and 10\ua0years (n\ua0=\ua0125).Although cohort subjects produced an average of 2.6\ua0±\ua00.3 of the 17 innate interferons tested at birth, 24% showed no T1/3IFN production. This nonproducer subgroup showed increased risk for infant fLRIs (odds ratio, 2.62; 95% CI, 1.14-6.06; P\ua0=\ua0.024) and persistent wheeze (odds ratio, 4.24; 95% CI, 1.60-11.24; P\ua0=\ua0.004) at age 5\ua0years relative to those producing 1 or more T1/3IFNs, whereas risk for infant wheezy lower respiratory tract infections or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRIs subsequently demonstrated accelerated development of T1/3IFN response capacity between 1 and 4\ua0years of age.T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory tract infections during infancy and subsequent persistent wheeze