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Background Models that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma. Objective To characterize the patterns of peripheral blood mononuclear cells' ( PBMCs) cytokine responses to house dust mite ( HDM) allergens among children from two population-based birth cohorts using machine learning techniques. Methods PBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study ( n = 268) and at 14 years of age from the Australian Raine Study ( n = 1374) were cultured with HDM extract (10 μg/ml). Cytokine expression ( IL-13, IL-5, IFN-γ, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping. Results A six-class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: ' Nonresponders' ( n = 905, 55%); ' IL-10 responders' ( n = 49, 3%); ' IFN-γ and IL-13 medium responders' ( n = 56, 3.4%); ' IL-13 medium responders' ( n = 351, 21.4%); ' IL-5 and IL-13 medium responders' ( n = 77, 4.7%); and ' IL-13 and IL-5 high responders' ( n = 204, 12.4%). ' IL-13 and IL-5 high responders' were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma. Conclusion Using model-based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL-13 and IL-5), and clinical outcomes. ' IL-13 and IL-5 high responders' class was strongly associated with HDM sensitization. However, among HDM-sensitized children, one-third showed no PBMC response to HDM, and the majority of HDM-sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM 'allergy tests' and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine-targeted treatment approaches. [ABSTRACT FROM AUTHOR] more...

To cite this article: Martino DJ, Bosco A, McKenna KL, Hollams E, Mok D, Holt PG, Prescott SL. T-cell activation genes differentially expressed at birth in CD4+ T-cells from children who develop IgE food allergy. Allergy 2012; 67: 191-200. Abstract Background: Presymptomatic immaturity in neonatal T-cell function is a consistent antecedent of allergic disease, including reduced responsiveness to polyclonal activation. Methods: To elucidate the underlying mechanisms, we examined for differences in T-cell gene expression in longitudinal samples collected at birth and at 1 year of age in children with ( n = 30) and without IgE-mediated food allergy ( n = 30). We employed a low-level soluble anti-CD3 stimulus to activate the T-cell receptor (TCR) and surveyed gene expression by DNA microarray in purified CD4+ T-cells. Allergen-specific responses were assessed in parallel functional studies. Results: At birth, the allergic group showed a reduced number of genes up regulated in response to anti-CD3 treatment on the microarray and a reduced lympho proliferative capacity, suggesting clear differences in T-cell signalling pathways. Polymerase chain reaction (PCR) validation of candidate genes confirmed significantly lower expression of a number of genes in the allergic group including RELB, NFKB2, LIF and FAS. By 12 months of age, there were marked changes in the anti-CD3 response in all infants, culminating in upregulation of cytokine genes (IL-5, IL-13, IL-17 and IL-22). Neonatal differences were no longer apparent. Instead, the allergic group, all symptomatic by this age, showed differential expression of T-cell lineage pathways including GATA-3, MAL and FcER1 in unstimulated T-cells. Allergen stimulation induced significantly higher cytokines production (IL-5, IL-13 and IFNγ) in the allergic group. Conclusion: Although transient, suboptimal neonatal T-cell activation pathways that signal through the NF-κB complex may affect the developmental transition of T-cell phenotypes in the periphery shortly after birth and may increase the risk of food allergy. [ABSTRACT FROM AUTHOR] more...