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Recently, we have demonstrated that anti-ulcer drugs, such as H2-receptor blockers and proton pump inhibitors, promote the development of immediate type food allergy toward digestion-labile proteins in mice. The aim of this study was to examine the allergological relevance of these findings in humans. In an observational cohort study, we screened 152 adult patients from a gastroenterological outpatient clinic with negative case histories for atopy or allergy, who were medicated with H2-receptor blockers or proton pump inhibitors for 3 months. IgE reactivities to food allergens before and after 3 months of anti-acid treatment were compared serologically. Ten percent of the patients showed a boost of preexisting IgE antibodies and 15% de novo IgE formation toward numerous digestion-labile dietary compounds, like milk, potato, celery, carrots, apple, orange, wheat, and rye flour. Thus, the relative risk to develop food-specific IgE after anti-acid therapy was 10.5 (95% confidence interval: 1.44-76.48). The long-term effect was evaluated 5 months after therapy. Food-specific IgE could still be measured in 6% of the patients, as well as significantly elevated serum concentrations of ST2, a Th2-specific marker. An unspecific boost during the pollen season could be excluded, as 50 untreated control patients revealed no changes in their IgE pattern. In line with our previous animal experiments, our data strongly suggest that anti-ulcer treatment primes the development of IgE toward dietary compounds in long-term acid-suppressed patients.

Our experimental and epidemiologic data suggest that the intake of antiulcer drugs may lead to the induction of immediate-type food hypersensitivity toward hazelnut.

In type I allergy, the cross-linking of membrane IgE on B lymphocytes and of cytophilic IgE on effector cells by their respective allergens are key events. For cross-linking two IgE molecules, allergens need at least two epitopes. On large molecules, these could be different epitopes in a multivalent, or identical epitopes in a symmetrical, fashion. However, the availability of epitopes may be limited on small allergens such as Bet v 1, the major birch pollen allergen. The present work analyzes whether dimerization is required for the cross-linking capacity of this allergen. In immunoblots, murine monoclonal and polyclonal human Bet v 1-specific Abs detected, besides a Bet v 1 monomer of 17 kDa, a dimer of 34 kDa. In dynamic light scattering, Bet v 1 appeared as dimers and even multimers, but a single condition could be defined where it behaved exclusively monomerically. Small-angle x-ray scattering of the monomeric and dimeric samples resulted in diagrams agreeing with the calculated models. Circular dichroism measurements indicated that the structure of Bet v 1 was preserved under monomeric conditions. Skin tests in Bet v 1-allergic mice were positive with Bet v 1 dimer, but remained negative using the monomer. Furthermore, in contrast to dimeric Bet v 1, the monomer was less capable of activating murine memory B cells for IgE production in vivo. Our data indicate that the presentation of two identical epitopes by dimerized allergens is a precondition for cross-linking of IgE on mast cells and B lymphocytes.

The treatment of dyspeptic disorders with anti-acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30-50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti-acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti-acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish-specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensitization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these offspring we found a relative Th2-dominance, because the Th1-and T-regulatory cytokines were significantly suppressed. Our data provide evidence that the anti-acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2-milieu in their offspring. From these results we propose that anti-acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants. Keywordssensitization against food; sucralfate; digestion; children; lactation The incidence of food allergies has been steadily increasing in the past decades and these allergies now affect ~3.5-4% of the adult population in the United States(1) and ~2.2-5.5% of children in the first year of life (2). Apart from several environmental influence factors, no genuine explanation accounts for this high number of children with food sensitization. It is known that the risk for sensitization in the offspring is higher when one or both parents, but especially when the mother is atopic (3). This may be due to hereditary factors, but an atopic mother may also transfer factors that directly bias the immune response of the infant to an allergic phenotype. For the adult population, we could show in previous studies that the risk to develop sensitization against food allergens increases with the usage of acid-suppressing drugs (4, 5), which are applied for the treatment of dyspeptic disorders such as gastric reflux, heartburn, and gastritis. We suggested that the hindered peptic digestion due to the elevated pH in the stomach leaves bigger fragments of alimentary proteins. These proteins could then elicit allergy due to persistence of their native conformation. © FASEBApproximately two-thirds of pregnant women suffer from heartburn and reflux due to low esophageal sphincter pressure, which is caused by changes of the hormone status (6). For their treatment, Richter suggested a step-up algorithm beginning with lifestyle modifications and dietary changes. As the first-line medical treatment antacids and sucralfate are used (7). The same review states that actually ~30-50% of women use antacids to relieve heartburn and other acid-reflux symptoms during pregnancy. For sucralfate, another nonabsorbable drug like antaci...

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Allergen-loaded PLGA nanoparticles modulate an ongoing Th2 response in the BALB/c mouse model, as demonstrated by down-regulation of IgG1 and production of IFN-gamma and IL-10. Our data strongly suggest that PLGA nanospheres can advantageously be used for formulations of allergen extracts or allergen derivatives for the few-shot treatment of type I allergy.

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