IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 23. Hypersensitivity - Type I

GENETICS OF HUMAN ALLERGIC REACTIONS

In the 1920s, it was established that children of allergic parents are more likely to exhibit allergic reactions than children of healthy parents. Indeed, if both parents suffer from allergies, the probability of their children developing an allergy is 50%; if one parent is affected, it is approximately 30%. Thus, a family history of allergy is a risk factor for atopy. However, twin studies indicate that The Development of atopic diseases is not entirely dependent on genetic factors (Fig. 23.7).

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Fig. 23.7. 1. Atopy is very common in individuals with a family history of allergies. As large-scale studies show, the stronger the family history of allergy, the higher the probability of atopy in children. 2. The concordance rate for atopic diseases in dizygotic (DZ, non-identical) twins is higher than in the general population (approximately 30%). However, the concordance rate in monozygotic (MZ, identical) twins is well below 100%—the probability that would be expected if the development of atopy were determined solely by genotype. These two facts indicate that the manifestation of atopic disease depends on both genetic and environmental factors.

The onset of allergies is significantly associated with various environmental factors, such as the degree of allergen exposure, diet, and chronic infections or acute viral diseases. Regarding the degree of exposure, the annual airborne pollutant dose per person is approximately 1 μg. It is perhaps remarkable that about 30% of the population react to such a low dose of airborne chemical pollutants.

Genetic mechanisms regulate three aspects of the allergic response:

✵ the total IgE level,

✵ the response Specificity to a given allergen, and

✵ generalized hyperreactivity.

Total IgE levels are genetically determined

Family and twin studies clearly demonstrate that total body IgE levels are genetically determined. Since the IgE response is favored by TH2 Cells and their secreted cytokines, it seems logical to search for an association between genetic markers in the "IL-4 Gene cluster" region and both total and specific IgE levels. Marsh's group conducted relevant studies and confirmed the existence of such an association. These authors demonstrated that IL-4 and/or products of other genes in this region of the long arm of chromosome 5 regulate total IgE levels (but not specific IgE content). Notably, other regions on the long arm of chromosome 5 may also play a role in regulating bronchial hyperresponsiveness by controlling the β₂-adrenergic receptor gene. Furthermore, it has been established that a potential marker for asthma and atopic sensitivity is localized to chromosome 11q13. This marker appears to be associated with a polymorphism of the FcεRI β chain.