IMMUNOLOGY - Roit A. - Mir 2000

Chapter 23. Hypersensitivity - Type I

GENES CONTROLLING ALLERGEN-SPECIFIC RESPONSES ARE LINKED TO HLA

The primary regulation of allergen-specific IgE responses appears to be mediated by HLA-linked Immune Response (IR) genes. This is most evident in responses to very low doses of allergens, particularly minor, low-molecular-weight determinants. For example, over 90% of individuals who mount an IgE response to the ragweed allergen Amb a V (5 kDa) carry HLA-Dw2 (Fig. 23.8). In contrast, no such HLA association has been found for the IgE response to the larger and more abundant Amb a I allergen (38 kDa).

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Fig. 23.8. HLA association of the IgE response to ragweed and ryegrass allergens.

The production of IgE Antibodies and immediate hypersensitivity Skin reactions show a stronger association with HLA than does the production of IgG antibodies. However, following hyposensitization to ragweed allergens, a prominent IgG response is observed exclusively in individuals with the HLA-Dw2, Amb a V⁺ genotype; this demonstrates that the Immune Response to Amb a V is not restricted to IgE production, but also involves other immunoglobulin classes.

Finally, an even stronger link between allergy and HLA type is observed when total IgE levels are low. For instance, among ragweed-allergic individuals, only one in six reacts to the minor determinant Amb a III, yet among those who do react and have low total IgE levels, 90% carry HLA-A2 (Fig. 23.9). As total IgE levels rise, this HLA association diminishes.

Fig. 23.9.

1. A chart showing the number of ragweed-allergic individuals (Amb a III⁺) at given total IgE levels; the range quartiles are indicated by different colors.

2. A chart showing the percentage of HLA-A2-positive individuals (both Amb a III⁺ and Amb a III^-) across the four quartiles. There is a clearly increased probability of reacting to Amb a III in HLA-A2 carriers. This relationship is most pronounced at low IgE levels. The HLA-A2 genotype is present in 47% of the population.

General and Specific hypersensitivity are associated with HLA

Hypersensitivity is considered general when skin test results are positive for a wide spectrum of allergens. Studies show that individuals with general hypersensitivity carry HLA-B8 and HLA-Dw3 genotypes (though not HLA-A1) with a significantly higher frequency than healthy controls.

Among individuals who already possess IgE antibodies to ragweed allergens, those with even more specific hypersensitivity can be identified, and in HLA-B8 carriers, both antibody titers and total IgE levels are particularly high.

The HLA-B8 genotype has also been found to exhibit a strong association with Other forms of immune "hyperactivity," such as autoimmune diseases. This suggests that HLA-B8 is somehow involved in T-Cell suppressor Regulation of the immune response, given that impaired suppressor cell activity is believed to play a role in the Pathogenesis of both autoimmune disorders and IgE responses.