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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 25, 2005 as doi:10.1096/fj.04-3170fje. |
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* Center of Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria;
# Department of Dermatology, Hetényi Géza Hospital, Szolnok, Hungary; and
Center for Public Health, and
Department of CT-Surgery, Medical University of Vienna, Vienna, Austria
2Correspondence: Center of Physiology and Pathophysiology, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: erika.jensen-jarolim{at}meduniwien.ac.at
SPECIFIC AIMS
Food allergens that are able to sensitize via the gastrointestinal tract are postulated to be digestion stable. We have observed that dietary proteins lead to allergic reactions in BALB/c mice only when their B cell epitopes are stabilized. Strikingly, some typical food allergens like fish, shrimp, and potato are easily degraded when subjected to simulated gastric fluid assays. Our consequent hypothesis was that proteins might exhibit allergenic capacity not only when digestion resistant, but also when simply surviving the gastric transit. Indeed, gastric acid suppression through H2 receptor blockers and proton pump inhibitors hindered pepsin activation and led to IgE formation toward undigested proteins in mice. In the present study we aimed to evaluate whether this mechanism may also cause food hypersensitivities in acid-suppressed patients.
PRINCIPAL FINDINGS
1. A 3 month medication with anti-ulcer drugs induces a boost or de novo IgE formation toward dietary antigens in gastroenterological patients
For our study, 152 gastroenterological patients (mean age 65.9 years) who were treated with H2 receptor blockers or proton pump inhibitors for 3 months of were recruited based on precise inclusion criteria. Blood samples were drawn before and after 3 months of therapy, and levels of IgE specific for 19 different foods were analyzed by immunoblot. Three months of anti-ulcer therapy resulted in an increase in food-specific IgE in 25% of all treated patients, due either to a boost of preexisting food-specific IgE in 10% or de novo IgE formation in 15% (Fig. 1
). The increases were statistically significant for peanut, walnut, almond, potato, tomato, celery, carrot, orange, wheat flour, and rye flour. Fifty age-matched healthy controls were followed up to assess any seasonal effects: one developed IgE toward a single food allergen; in all other subjects IgE levels remained unchanged. Hence, the relative risk for the increase of an IgE response to food allergens after a 3 month anti-acid therapy is 10.5 (95% confidence interval: 1.44–76.48; P=0.0203).
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2. Digestion-labile dietary antigens harbor sensitizing capacity when gastric digestion is hindered
Simulated gastric fluid (SGF) experiments are a means to predict the allergenicity of food antigens through their resistance to gastric digestion. When 19 regular food antigens were subjected to SGF treatment, potato, celery, carrot, apple, orange, wheat flour, rye flour, codfish, and crab proteins were degraded within 1 min as evaluated by SDS-PAGE, whereas casein, egg white, egg yolk, almond, and tomato proteins resisted enzymatic digestion for up to 30 min. The most resistant proteins were found in peanut, walnut, sesame seed, and soy, which were still detectable after 2 h of digestion. That means that potato, celery, carrot, orange, and wheat and rye flour, according to the SGF test, do not harbor gastric sensitization properties, but were still responsible for de novo IgE induction in 11.8% of all patients. Cross reactivity phenomena could be ruled out as these patients did not exhibit concomitant inhalative sensitization.
3. Anti-ulcer treatment induces long-term sensitization and increases in ST2 levels
Five months after discontinuation of anti-ulcer treatment, food-specific IgE could be detected in 6% of the 152 patients’ sera (compared with 25% at 3 months). Their IgE levels were still significantly elevated against potato, tomato, celery, carrot, orange, and wheat flour (P values between 0.027 and 0.046) compared with values before therapy. Performing skin prick tests using a panel of 19 food antigens showed that 7.02% of the skin tests (44 of 627) were positive. In controls, only 1.00% of positive wheal and flare reactions were elicited (8 of 798 pricks). Skin reactivity correlated with sensitization patterns seen in the individual patients with specific IgE in immunoblots, validated by a UniCAP assay with randomly selected sera.
To determine whether this long-term sensitization was paralleled by changes in cytokine levels, we compared the serum concentrations of IL-4, IFN-
, and IL-13 in 20 randomly selected patients and 20 controls. No statistically significant differences of cytokine levels were observed between the two groups (Table 1
). ST2 was selected as a marker for Th2 lymphocyte activity. Here, a major difference between the groups was observed: Soluble ST2 in sera of patients was significantly higher than in the sera of control group (P=0.016, Table 1
).
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CONCLUSIONS AND SIGNIFICANCE
We describe here a link between long-term therapy with anti-ulcer drugs (e.g., H2 receptor blockers and proton pump inhibitors) and sensitization to food antigens. After 3 months of acid suppression treatment, in 25% of the 152 patients, food-specific IgE increased with respect to quality and/or quantity of binding. 15% showed even de novo IgE formation toward food compounds without concomitant pollen sensitization. A previous publication has shown that in a random sample from the general adult population 6% had specific IgE to the food antigens tested. Therefore, we reason that the increase of food-specific IgE antibodies observed may be associated with the impaired gastric digestion during treatment with anti-ulcer drugs.
An appreciable number of sensitizations was directed against food proteins, which were easily degraded in simulated gastric fluid experiments. Digestion assays are standard safety tests for determining the allergenic potential of food compounds. Proteins resisting peptic digestion have a much higher sensitization potential and are termed "class 1 food allergens," whereas digestion-sensitive antigens are doubted to harbor sensitizing capacity and are often termed "incomplete" allergens or "nonsensitizing elicitors." Our data indicate that digestion-labile proteins may also sensitize via the gastrointestinal tract and lead to IgE induction in settings where peptic digestion is hindered. Sensitization toward foods thus occurred during anti-ulcer therapy, but the extent of IgE reactivity decreased after its discontinuation. Obviously, IgE production is boosted only in times of digestion incapability, when proteins remain conformationally intact. After 5 months off the medication, the patients’ serum IgE to food proteins had decreased, but positive reactions in skin prick testing were still seen. IgE has a prolonged half-life when bound to Fc
RI-positive cells. We suggest that this phenomenon is responsible for the "tissue memory" noted.
Previous cohort studies have estimated that 10–15% of the adults regularly consume anti-ulcer drugs and 0.82% of a general practice population are treated in a long-term fashion (>6 months) even without a confirmed diagnosis of dyspeptic diseases. Obviously, these drugs belong to the bestsellers of the pharmaceutical companies, and sales figures in the U.S. are on the rise since H2 receptor blockers and proton pump inhibitors have been approved for over-the-counter sale. Both drugs reduce the net gastric acid output. Five days of treatment with Omeprazole are sufficient to elevate the gastric pH to an average of 5.0. Notably, total enzyme activity for the different pepsins in gastric juices has an optimum pH range between 1.8 and 3.2. Therefore, any increase in gastric pH not only interferes with the protective role of gastric acid itself, but has major implications on the digestive function of the stomach.
Our results indicate that the stomach fulfils an important biological gatekeeping function via acid-dependent peptic digestion. Under hypoacidic conditions, peptic digestion is hindered; dietary proteins keep their sensitization capacity and may elicit food hypersensitivity (Fig. 2
). Risk assessment tests for the allergenicity of food proteins based on simulated gastric fluid experiments thus are not applicable for situations of elevated gastric pH. From our data we conclude that long-term acid suppressed patients may develop Th2-biased hypersensitivities.
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FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-3170fje; doi: 10.1096/fj.04-3170fje
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