Random allergen-specific IgE expression in atopic families: Evidence for inherited ‘stochastic bias’ in adverse immune response development to non-infectious antigens

Abstract

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. Heritabilty 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.

Introduction

Atopic disorders, such as allergic rhinitis and bronchial asthma, are common complex human diseases. Epidemiological studies have shown that adverse IgE-mediated immune responses are significant risk factors for these conditions (Pearce et al., 1999). And, due to their tendency to cluster within families, they have a significant inherited component (Blumenthal and Björkstén, 1997). Results of numerous genome-wide screens and case-control studies have shown multiple chromosomal regions with suggestive associations to these conditions (Hoffjan et al., 2003). But, there is no clear consensus with regard to either the genes involved (Altmüller et al., 2001) or the mode of inheritance for these conditions (Blumenthal and Björkstén, 1997).

Atopy is an adverse humoral immune response among some people to otherwise benign, non-infectious environmental antigens (allergens) involving the production of allergen-specific IgE. An assumption often made is that specific genes responsible for adverse IgE responses are inherited and passed along within families. However, aside from the possibility of multiple genetic contributions and random environmental modifications of their effects, regulation of IgE production involves numerous metabolic pathways (Geha et al., 2003). Different pathways imply different genes responsible for the outcomes.

Thus, a paradox arises of clinically well-defined diseases known to be inherited, but with no clearly discernible pattern for the genes responsible for their expressions. Two different models could account for these disease processes.

One model is that of obligate inheritance, in which it is postulated that there are specific inherited errors in the recognition and/or response to specific allergens, or possibly to allergens in general. In this case, there are assumed genetic errors in the regulation of IgE production leading to adverse responses to allergens. However, the particular regulatory pathways involved need not be the same in all families. This would account for common outcomes observed in population-based epidemiological studies, but a lack of consensus with regard to the “gene patterns” contributing to these disorders.

An alternate model is one of stochastic bias. In this case, it is assumed that the regulatory pathways are the same for everyone, but during the evolution of a particular response, temporary changes in physiological status (e.g. immunological skewing) may result in ‘errors’ leading to a pathological outcome. As with other metabolically complex processes, the underlying physiological mechanisms, like receptor–ligand interactions or biochemical feedback systems, are often non-linear with regard to stimulus–response coupling (Glass, 2001). On their own, the function of each pathway may be described in deterministic terms, but their complex interactions may lead to apparently random outcomes. In this model, inheritance is a ‘weighting factor’ contributing to these ‘errors,’ as it only promotes an increased likelihood of atopy arising within members of families, but is not an obligate occurrence.

Heritability estimates and gene searches for complex human diseases are based upon quantitative traits (phenotypes), such as serum total IgE, whose expression levels can be compared by standard statistical analyses among related individuals (Falconer and MacKay, 1996). An implicit assumption in these strategies is that the phenotype expression levels are normally distributed, arising from the influence of one or more genes. It is further assumed that a direct causal relationship exists between gene inputs and phenotypic trait expressions, resulting in positive correlations of trait expression values among members of kinships. Any variation from this assumption is most-often attributed to random environmental factors.

In this study, we analyzed the statistical inter-relationships among kinships for quantitative IgE traits known to be associated with atopy. We focused upon first-degree relatives (parent–child and sibling–sibling), as these were the most likely to demonstrate genetic effects with regard to IgE-mediated responses, and would be the least likely to be significantly influenced by random environmental impacts. Our objective was to determine which of two models most likely accounted for atopic immune responses in these kinships: obligate inheritance versus stochastic bias.

Overall, the results show that pathology-associated IgE outcomes cannot arise from simple causal stimulus–response coupling mechanisms. Rather, adverse physiological responses, like allergen-specific IgE, arise from mechanisms that alter the probabilities of isotype switching to IgE and result in random phenotype expressions among those who are clinically affected. Future studies related to the inheritance of these complex diseases will have to take these stochastic features into account.