Distinguishing benign from pathologic TH2 immunity in atopic children

Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms. Objective: We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children. Methods: In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass. Results: Among mite-sensitized children across all populations and at different ages, house dust mite-specific IgG/IgE ratios (but not IgG(4)/IgE ratios) were significantly lower in children with asthma compared with ratios in those without asthma and lowest among the most severely symptomatic. This finding was mirrored by relationships between rhinitis and antibody responses to grass. Depending on age/allergen specificity, 20% to 40% of children with allergen-specific IgE (sIgE) of 0.35 kU/L or greater had negative skin test responses, and these children also expressed the high sIgG/sIgE immunophenotype. sIgG(1) from these children inhibited allergen-induced IgE-dependent basophil activation in a dose-dependent fashion. Profiling of aeroallergen-specific CD4(+) T-H memory responses revealed positive associations between sIgG/sIgE ratios and IL-10-dependent gene signatures and significantly higher IL-10/T(H)2 cytokine (protein) ratios among nonsymptomatic children. Conclusion: In addition to its role in blocking T(H)2 effector activation in the late-phase allergic response, IL-10 is a known IgG(1) switch factor. We posit that its production during allergen-induced memory responses contributes significantly to attenuation of inflammation through promoting IgG(1)-mediated damping of the FceRI-dependent acute-phase reaction. sIgG(1)/sIgE balance might represent a readily accessible therapeutic target for asthma/rhinitis control.