No abstract

By adulthood there is almost universal immunological memory to aeroallergens, and the presence of allergic disease appears to be related to the nature of the underlying T-helper (Th) cell cytokine responses. The hypothesis of this study is that adult patterns of allergen specific Th-cell memory (Th-2 polarized in atopics vs. Th1 in non-atopics) can be determined in early infancy. Mononuclear cell cytokine responses to house-dust mite were measured at 6-monthly intervals from birth to 2 years of age, using ELISA (IL-10, IL-13, IFN-gamma) and sqRT/PCR (IL-4, IL-5, IL-9, IFN-gamma) in normal infants (n = 14) with no family history or allergic symptoms, and infants with a family history and definite atopy by 2 years (n = 16). Both normals and atopics showed low-level Th2 skewed allergen-specific responses at birth with little accompanying IFN-gamma. The Th2 responses to house-dust mite were higher in normal newborns, who then show a rapid downregulation of these responses in the first year of life. Atopic infants instead show a consolidation of their neonatal patterns of Th2 polarized allergen specific immunity. Earlier studies indicate that neonates at high risk of atopy display diminished capacity for production of the Th1 cytokine IFN-gamma. The present study suggests for the first time that neonates who subsequently develop atopy also initially have reduced capacity to mount Th2 responses. However, in contrast to non-atopics who selectively downregulate their fetal Th2 polarized allergen-specific responses, atopic children display age-associated upregulation of Th2 immunity.

Detailed analysis of cytokine responses in this very young age group have the potential to uncover subtle relationships between in vivo and in vitro allergen reactivity which may be less clear in adults, in whom T-cell response patterns are modified via chronic stimulation. The present findings which suggest potentially important roles for IL-9 and IL-10 in the early phase of allergic disease, may be one such example.

There are few studies on allergen-induced cytokine production in allergic children, and little is known of antigen-specific cytokine regulation of human immunoglobulin (Ig) G subclass antibody responses. An association with T-helper 1 (Th1)-like immunity and complement-activating antibodies remains to be demonstrated in humans. We have previously observed that atopic symptoms are associated with high levels of IgG subclass, especially IgG4, antibodies to birch and beta-lactoglobulin. The differences were seen early in life for the food allergen and increased with age for the inhaled allergen. The aim of this study was to investigate the association between atopic symptoms, birch allergen-, and beta-lactoglobulin-induced cytokine production in peripheral blood mononuclear cells (PBMC), and serum IgE and IgG subclass antibody responses to these allergens in children in order to further clarify the role of Th1- and Th2-like immunity in responses to various antigens. PBMC from 55 eight-year old children, who had been followed prospectively from birth, were stimulated with birch- and beta-lactoglobulin. Production of interleukin (IL)-5, IL-6, IL-10, IL-13 and interferon (IFN)-gamma was analysed by ELISA and expression of IL-4 and IL-9 mRNA by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). IgG subclass antibody levels to birch- and beta-lactoglobulin in serum were determined by ELISA, and IgE antibodies by Magic-Lite and CAP-RAST, respectively. Birch-induced expression of IL-4, but not of the other cytokines, was associated with IgE antibodies to birch. Furthermore, the IL-4 expression and IL-6 production correlated with serum IgG4 antibody levels to this allergen, and IFN-gamma secretion with IgG1 antibody responses. There were no correlations between beta-lactoglobulin-stimulated cytokine production and IgG subclass antibody levels to that allergen, except for a negative association between beta-lactoglobulin-stimulated IL-4 expression and IgG1 antibodies. Atopic children tended to have high levels of birch and beta-lactoglobulin-induced IL-5, IL-6 and IL-10 secretion. Birch-induced IL-4 expression may be the major factor in determining IgE antibody formation to that allergen, while allergen-induced IL-5, IL-6 and IL-10 secretion in PBMC is associated with atopic symptoms. Th1-like immunity to inhaled allergens could be associated with production of the opsonizing and complement-activating IgG1 antibody subclass, and Th2-like immunity with IgG4 antibody responses.

These findings identify Th2-associated TFs as key determinants of the atopic phenotype, suggesting their unique potential as therapeutic targets for disease control.