Random allergen-specific IgE expression in atopic families: evidence for inherited "stochastic bias" in adverse immune response development to non-infectious antigens.

The complex inherited human atopic diseases are associated with adverse IgE-mediated immune responses, notably allergen-specific IgE that presumably involves the input from one or more genes. However, gene searches have met with limited success, possibly because a causally direct gene input-trait outcome assumption is not valid for these immune responses. To test this assumption, we determined the probability distributions of quantitative IgE responses associated with atopy, and used these to determine the statistical interdependence among first-degree relatives (parent-child and sibling-sibling) from families with history of atopic asthma (total available N=1099). Each person was screened for asthma history, pulmonary responses by spirometry and atopic immune responses using serum total IgE and skin prick tests (SPT) to 14 allergens. Heritability estimates were made by variance components analysis for quantitative IgE traits. The serum total IgE distribution comprised statistically independent sub-sets when individuals were categorized as either SPT [-] or SPT [+], reflecting contributions from non-pathology associated basal IgE and pathology-associated allergen-specific IgE. However, heritability estimates were significant only for basal IgE, while total allergen-specific IgE production was a random variable independent of inheritance. Genes for specific IgE-mediated responses are not obligately inherited. Rather, gene products that modulate underlying stimulus-response coupling interactions and alter the probabilities influencing adverse immune responses are inherited, but an individual's specific pathologic outcome is a random variable. These results support a model of "stochastic bias" that "skews" an immune response to non-infectious antigens among people with an inherited predisposition for atopy.