Isabella Schöll

Antacid medication inhibits digestion of dietary proteins and causes food allergy: A fish allergy model in balb/c mice

BACKGROUND Digestible proteins were supposed to be irrelevant for oral sensitization and induction of food allergy. Approximately 10% of the adult population uses antacids for the treatment of dyspeptic disorders, drugs that hinder peptic digestion. In these patients, proteins that are normally degradable might act as food allergens. OBJECTIVE We aimed to study the influence of antacid intake on the allergenicity of dietary proteins, taking sturgeon caviar and parvalbumin, the major fish allergen, as examples. METHODS Caviar proteins and recombinant parvalbumin from carp, rCyp c 1, were applied for intragastric feedings with or without the antacids sucralfate, ranitidine or omeprazole, using a Balb/c mouse model. RESULTS Both caviar proteins and parvalbumin were rapidly degraded in an in vitro digestion assay at pH 2.0, but not at pH 5.0, imitating the effect of antacids. The groups fed with caviar in combination with ranitidine hydrochloride intramuscularly or sucralfate orally had significant levels of caviar-specific IgE antibodies (P <.01), T-cell reactivity, and elevated counts of gastrointestinal eosinophils and mast cells. Food allergy in these groups was further evidenced by oral provocation tests and positive immediate-type skin reactivity. In contrast, feedings with caviar alone led to antigen-specific T-cell tolerance. None of the groups showed immune reactivity against the daily mouse diet. As a proof of the principle, feeding mice with parvalbumin in combination with ranitidine or omeprazole intramuscularly induced allergen-specific IgE antibodies (P <.05). CONCLUSIONS When antacid medication impairs the gastric digestion, IgE synthesis toward novel dietary proteins is promoted, leading to food allergy.

Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients

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 digestionlabile 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.

Dimerization of the Major Birch Pollen Allergen Bet v 1 Is Important for its In Vivo IgE-Cross-Linking Potential in Mice

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.

Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring

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 sensi‐tization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these off‐spring we found a relative Th2‐dominance, because the Thl‐ and T‐regulatory cytokines were significantly sup‐pressed. 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.—Schöll, I., Ackermann, U., Özdemir, C., Blümer, N., Dicke, T., Sel, S., Sel, S., Wegmann, M., Szalai, K., Knittelfelder, R., Untersmayr, E., Scheiner, O., Garn, H., Jensen‐Jarolim, E., Renz, H. Anti‐ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2‐bias in their offspring. FASEB J. 21, 1264–1270 (2007)

Allergenic Potency of Spices: Hot, Medium Hot, or Very Hot

Spices are the most attractive ingredients to confer an authentic taste to food. As they are derived from plants, they harbour allergenic potency and can induce symptoms ranging from mild local to severe systemic reactions. Due to the content of pharmacologically active substances of spices, the diagnosis of allergy and the differentiation from intolerance reactions may be difficult. Association with inhalative allergies via IgE cross-reactivity, but also direct gastrointestinal sensitization plays a role. This article is a botanical and allergological overview of the most important spices and molecules responsible for eliciting IgE-mediated reactions or cross-reactions. As no curative treatments are known at present, strict avoidance is recommended and, therefore, accurate labelling of pre-packed food is necessary.

Monovalent fusion proteins of IgE mimotopes are safe for therapy of type I allergy

By screening phage display random peptide libraries with purified immunoglobulin E (IgE) from birch pollen‐allergic patients, we previously defined peptides mimicking natural IgE epitopes (mimotopes) of the major birch pollen allergen Bet v 1. The present study aimed to define a monovalent carrier for the IgE mimotopes to induce protective antibodies directed to the IgE epitopes, suitable for mimotope‐specific therapy. We expressed the selected mimotopes as fusion proteins together with streptococcal albumin binding protein (ABP). The fusion proteins were recognized specifically by anti‐Bet v 1 human IgE, which demonstrated that the mimotopes fused to ABP resemble the natural IgE epitope. Bet v 1‐specific IgG was induced by immunization of BALB/c mice with fusion proteins. These IgG antibodies could inhibit IgE binding to Bet v 1. Skin testing of Bet v 1 allergic mice showed that the ABP mimotope constructs did not elicit type I skin reactions, although they possess IgE binding structures. Our data suggest that IgE mimotopes are safe for epitope‐specific immunotherapy of sensitized individuals, when presented in a monovalent form. Therefore, ABP‐fused mimotopes are promising candidates for a new type of immunotherapy based on the precise induction of blocking antibodies.

Occupational sensitization to ribosome-inactivating proteins in researchers

Background Ribosome‐inactivating proteins (RIPs) are expressed in many plants. Because of their anti‐infectious and anti‐proliferative effects, intensive research is going on for applying these toxins in therapy against viral infections or malignancies. Recently, we demonstrated that type I allergy against RIPs from elderberry can occur.

CD4+ T cells from mice with intestinal immediate‐type hypersensitivity induce airway hyperreactivity

Background A subset of food‐allergic patients does not only respond clinically with symptoms in the gastro‐intestinal tract but also with asthmatic reactions.

Mimotope und ihre Bedeutung für die Allergologie

ZusammenfassungHintergrundAntiallergen- und Anti-IgE-Antikörper können die allergische Symptomatik inhibieren oder verstärken. Diese Effekte sind von der Epitopspezifität abhängig.MethodikRekombinante Phagen-Display-Peptid-Bibliotheken enthalten Hunderte Millionen von Zufallspeptiden. Mit der Biopanning-Technik werden durch Antikörper daraus Peptide selektioniert, die das natürliche Epitop nachahmen und daher Mimotope genannt werden. Vergleiche der Mimotope mit dem natürlichen Antigen (Allergen) erlauben die Lokalisation des Epitops und geben somit Aufschluss über antigene Strukturen. Mimotope können des Weiteren für Immunisierungen zur Induktion einer aktiven epitopspezifischen Immunantwort herangezogen werden.SchlussfolgerungDie AAmbivalenz der natürlichen IgG-Antikörper (Blockierung oder Verstärkung der allergischen Reaktionen), welche bei der spezifischen Immuntherapie induziert werden, erfordert den Zuschnitt der Impfstoffe für Typ-I-Allergien auf epitopspezifische Vakzinen. Mimotope sind geeignete Kandidaten für die Realisierung dieses epitopspezifischen Impfkonzepts.SummaryBackgroundAnti-allergen and anti-IgE antibodies may enhance or inhibit allergic reactions. These effects do critically depend on their epitope specificity.MethodsRecombinant phage-display peptide libraries contain hundreds of millions of random peptides. Biopanning is a procedure suitable to select specifically binding peptides from these libraries, which mimic the natural antigen and, therefore, are called mimotopes. Alignments of the mimotopes with the three-dimensional structure of the antigen or allergen allow to localize the epitope and give remarkable insights into antigenic and allergenic determinants. Moreover, mimotopes may be applied therapeutically for the precise induction of epitope-specific antibody responses.ConclusionNatural IgG antibodies induced through hyposensitization therapy harbor diverse biological effects (inhibiting or enhancing allergic responses). Therefore, vaccines applied for the treatment of type I allergy should be tailored in an epitope-specific way. Mimotopes are suitable candidates for realizing this concept of epitope-specific immunotherapy.

Monovalent fusion proteins of IgE mimotopes are safe for therapy of type I allergy 1

By screening phage display random peptide libraries with purified immunoglobulin E (IgE) from birch pollen‐allergic patients, we previously defined peptides mimicking natural IgE epitopes (mimotopes) of the major birch pollen allergen Bet v 1. The present study aimed to define a monovalent carrier for the IgE mimotopes to induce protective antibodies directed to the IgE epitopes, suitable for mimotope‐specific therapy. We expressed the selected mimotopes as fusion proteins together with streptococcal albumin binding protein (ABP). The fusion proteins were recognized specifically by anti‐Bet v 1 human IgE, which demonstrated that the mimotopes fused to ABP resemble the natural IgE epitope. Bet v 1‐specific IgG was induced by immunization of BALB/c mice with fusion proteins. These IgG antibodies could inhibit IgE binding to Bet v 1. Skin testing of Bet v 1 allergic mice showed that the ABP mimotope constructs did not elicit type I skin reactions, although they possess IgE binding structures. Our data suggest that IgE mimotopes are safe for epitope‐specific immunotherapy of sensitized individuals, when presented in a monovalent form. Therefore, ABP‐fused mimotopes are promising candidates for a new type of immunotherapy based on the precise induction of blocking antibodies.