Random allergen-specific IgE expression in atopic families: Evidence for inherited ‘stochastic bias’ in adverse immune response development to non-infectious antigens
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.
Section snippets
Study population
Families that included two children with a physician's diagnosis of asthma were recruited as previously described (CSGA, 1997). This included 666 members of 26 multi-generation families and 433 members of small nuclear families. Each person, or legal guardian, provided written, informed consent according to the guidelines of the Institutional Review Board of the University of Minnesota. Participants were given a routine physical examination, an interviewer-monitored questionnaire, prepared
Study population demographics
A total of 1099 Caucasians from families with history of atopic asthma residing in Minnesota were screened. As shown in Table 1, the study population comprised 666 individuals from 26 multiplex families, with representatives from 2 to 4 generations per family, and 433 people from 110 small nuclear families. Overall, there were roughly equal numbers of females and males, with ages spanning roughly seven decades.
As described in Methods, each person was screened for asthma history, evidence of
Discussion
The objective of this study was to determine which of two alternative models best accounts for expressions of allergen-specific IgE immune system outcomes in families with significant histories of atopic diseases. One model, obligate inheritance, postulates that there are specific inherited genetic alterations resulting in abnormal recognition and/or response to allergens that would directly influence the expression levels of quantitative IgE traits. If correct, then there should be significant
Acknowledgements
Supported by N.I.H. grant 2 RO1-HL-049609-11 and the Asthma and Allergy Research Fund, Department of Medicine, University of Minnesota (Malcolm N. Blumenthal, M.D., Director). We gratefully acknowledge Andreas Rosenberg, Emeritus Professor, University of Minnesota for a critical reading of the manuscript.
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