The results presented here provide extensive evidence that a specific IgE antibody response to an oligosaccharide common to all nonprimate mammals does not create a risk for asthma. Through examination of patients in Virginia with IgE to α-gal, patients presenting with asthma to the ED in Charlottesville, or children in a Kenyan village, it is clear that having this antibody is not related to lung inflammation or symptoms. Given that sensitization to cat allergens has been consistently associated with asthma, it was a surprise to find a large number of patients presenting with recurrent anaphylaxis or urticaria who had positive skin tests and serum assays to cat. As judged by symptoms, eNO, and lung function, few of these patients had asthma. This conclusion was supported by further investigation of two cohorts in which we had previously noticed a high prevalence of IgE antibodies to cat but no increased risk for asthma: the Charlottesville ED and Kenyan school children (13
). In each case, the apparently anomalous results for cat were explained by the finding of IgE antibodies to the oligosaccharide α-gal.
Allergens including house dust mite (Der p 1) and cat (Fel d 1) that clearly correlate with risk for asthma are proteins with a complex surface and multiple epitopes that favor binding of high-affinity IgE antibodies (31
); such protein allergens are able to induce positive skin tests with concentrations of purified proteins in the range of 10−3
μg/ml. In contrast, our own experience and a recent study reported positive skin tests in patients with IgE to α-gal using 5–50 μg/ml of cetuximab (33
). The blunted skin test response using this mammalian oligosaccharide is consistent with responses to skin testing in patients with IgE antibodies to plant oligosaccharides (34
). Given the small quantities of protein that actually enter the large and medium airways, it makes sense that an allergen that requires micrograms to produce a positive skin test would not give rise to inflammation in the lungs. The evidence reported here for the association between IgE antibodies to Fel d 1 and asthma in northern Sweden is in keeping with a model where allergen entering the lungs of a sensitized subject is able to cross-link IgE receptors on mast cells and trigger inflammation in the lungs. The role of Fel d 1 in asthma may also involve T-cell epitope-mediated recruitment of T cells that contribute to the pathogenesis of lung inflammation (36
). With regard to α-gal, the specificity of the T cells associated with this potential mechanism is not known. However, exposure to this epitope either as a food or inhalant is unlikely to occur on the same carrier as was involved in the initial tick-induced IgE antibody response. The lack of a relevant carrier could also contribute to the absence of a pulmonary response in these patients.
It has been consistently reported that total serum IgE is elevated among patients with asthma, but mixed opinions about the significance of this observation persist (5
). The IgE antibody response to α-gal may provide further insight in that it not only correlates strongly with total serum IgE, but also that this IgE response can represent a large proportion of the total IgE. In addition, we have documented specific IgE to α-gal and total IgE rising in parallel after tick bites (18
). Although it is well recognized that helminth infection can induce IgE antibodies, only limited studies on the specificity of these IgE antibodies or the quantitative contribution of these antibodies to total serum IgE have been reported (39
). As with other immunoglobulin isotypes and with other IgE responses, the specific IgE responses do not explain the total (40
). The important conclusion here is that this IgE antibody response to an oligosaccharide epitope is a “cause” of elevated total IgE in the United States and is nonetheless unrelated to asthma.
The results here explain the previously enigmatic finding of IgE antibodies to cat in Kenya and South Africa (13
). Several studies in Africa have reported the presence of sensitization to mite allergens that was not related to asthma (13
). However, those IgE antibody responses, where measured, were low in titer (13
). Recently, we have reported that a major effect of affluence among school children in Kumasi, Ghana, was increased titer of IgE antibodies to mite (41
). The evidence reported here about the influence of high-titer IgE antibody on asthma in Virginia and Sweden may help to explain the finding that low-level sensitization to mite in developing countries shows little relationship to allergic symptoms or asthma.
In a recent publication, we reported that the IgE antibody response to α-gal is primarily induced by tick bites, specifically those of the species A. americanum
(the Lone Star tick) in the southeastern United States (18
). This is an example of a parasite-induced IgE response that is common in a developed country. In contrast, we cannot make a convincing case about the cause of IgE responses to α-gal in Africa where children are exposed to many different parasites, including nematodes, cestodes, and a range of ectoparasites including ticks (13
). Previous studies have demonstrated that specific IgE antibodies that are pertinent to asthma can be correlated with total serum IgE (12
); here we have documented a specific IgE antibody response that is quantitatively related to total serum IgE, but not associated with asthma. Asthma is a heterogeneous disease state with multiple known factors influencing its development. Similarly, total serum IgE is now recognized to vary among individuals based on genetics alone (44
). Our findings, taken together with those of genetic studies, suggest that consideration of specific sensitizations is more pertinent to understanding risk for asthma than is total serum IgE.
The results for the 18 year olds in Sweden provide a negative control for the effects of helminths or ticks, because these parasites are very rare in the inland area of Norrbotten. In addition, those results emphasize that IgE antibody responses to α-gal are not induced by the oral route (e.g., eating red meat) or by any other form of contact with a domestic animal (e.g., living in a house with a cat). Thus, the Swedish data emphasize the importance of the form and route of exposure. In Virginia, this means exposure through the skin to the salivary proteins of an arthropod.
The primary objective of this report was to investigate the clinical relevance of IgE antibody responses to α-gal. However, the results address several related questions. First, it is clear that presenting an antigen through the skin can induce high-titer IgE antibody responses in humans and that these responses can give rise to allergic symptoms after exposure by a different route (oral exposure to red meat, in this case). Second, the results provide a model for parasite-related IgE responses that can contribute to high serum IgE without having an effect on respiratory allergic symptoms. Third, within the present and other recent studies, there is a consistent relationship between the titer of IgE antibodies to inhalant allergens and the risk of asthma (12
). These findings clearly do not exclude the possibility of a noninhaled antigen associating with asthma. The observations that α-gal is not airborne and having IgE antibodies to α-gal does not increase the risk for asthma, supports the view that those allergens most relevant to asthma pathogenesis are those that are inhaled.