Erika Jensen-Jarolim

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.

The role of protein digestibility and antacids on food allergy outcomes

Digestion assays with simulated gastric fluid have been introduced for characterization of food proteins to imitate the effect of stomach proteolysis on dietary compounds in vitro. By using these tests, dietary proteins can be categorized as digestion-resistant class 1 (true allergens triggering direct oral sensitization) or as labile class 2 allergens (nonsensitizing elicitors). Thus the results of these digestion assays mirror situations of intact gastric proteolysis. Alterations in the gastric milieu are frequently experienced during a lifetime either physiologically in the very young and the elderly or as a result of gastrointestinal pathologies. Additionally, acid-suppression medications are frequently used for treatment of dyspeptic disorders. By increasing the gastric pH, they interfere substantially with the digestive function of the stomach, leading to persistence of labile food protein during gastric transit. Indeed, both murine and human studies reveal that antiulcer medication increases the risk of food allergy induction. Gastric digestion substantially decreases the potential of food proteins to bind IgE, which increases the threshold dose of allergens required to elicit symptoms in patients with food allergy. Thus antiulcer agents impeding gastric protein digestion have a major effect on the sensitization and effector phase of 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.

Pasteurization of milk proteins promotes allergic sensitization by enhancing uptake through Peyer's patches.

Background:  The underlying mechanisms responsible for allergic sensitization to food proteins remain elusive. To investigate the intrinsic properties (as well as the effect of pasteurization) of the milk proteins α‐lactalbumin, β‐lactoglobulin and casein that promote the induction of milk allergy.

AllergoOncology: the role of IgE-mediated allergy in cancer

Epidemiological studies have suggested inverse associations between allergic diseases and malignancies. As a proof of concept for the capability of immunoglobulin E (IgE) to destruct tumor cells, several experimental strategies have evolved to specifically target this antibody class towards relevant tumor antigens. It could be demonstrated that IgE antibodies specific to overexpressed tumor antigens have been superior to any other immunoglobulin class with respect to antibody‐dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) reactions. In an alternative approach, IgE nonspecifically attached to tumor cells proved to be a powerful adjuvant establishing tumor‐specific immune memory. Active Th2 immunity could also be achieved by applying an oral immunization regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced IgE antibodies could be cross‐linked by live tumor cells leading to tumoricidic mediator release. Thus, IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings. Thereby, eosinophils, mast cells and macrophages can be armed with the cytophilic IgE and become potent anti‐tumor effectors, able to trace viable tumor cells in the tissues. It is strongly suggested that the evolving new field AllergoOncology will give new insights into the role of IgE‐mediated allergy in malignancies, possibly opening new avenues for tumor therapy.

Generation of Peptide Mimics of the Epitope Recognized by Trastuzumab on the Oncogenic Protein Her-2/neu

Immunizations with the oncogenic protein Her-2/neu elicit Abs exerting diverse biological effects--depending on epitope specificity, tumor growth may be inhibited or enhanced. Trastuzumab (herceptin) is a growth-inhibitory humanized monoclonal anti-Her-2/neu Ab, currently used for passive immunotherapy in the treatment of breast cancer. However, Ab therapies are expensive and have to be repeatedly administered for long periods of time. In contrast, active immunizations produce ongoing immune responses. Therefore, the study aims to generate peptide mimics of the epitope recognized by trastuzumab for vaccine formulation, ensuring the subsequent induction of tumor growth inhibitory Abs. We used the phage display technique to generate epitope mimics, mimotopes, complementing the screening Ab trastuzumab. Five candidate mimotopes were isolated from a constrained 10 mer library. These peptides were specifically recognized by trastuzumab, and showed distinctive mimicry with Her-2/neu in two experimental setups. Subsequently, immunogenicity of a selected mimotope was examined in BALB/c mice. Immunizations with a synthetic mimotope conjugated to tetanus toxoid resulted in Abs recognizing Her-2/neu in a blotted cell lysate as well as on the SK-BR-3 cell surface. Analogous to trastuzumab, the induced Abs caused internalization of the receptor from the cell surface to endosomal vesicles. These results indicate that the selected mimotopes are suitable for formulation of a breast cancer vaccine because the resulting Abs show similar biological features as trastuzumab.

The ABC of clinical and experimental adjuvants—A brief overview

Adjuvants are compounds that can increase and/or modulate the intrinsic immunogenicity of an antigen and elicit strong and long lasting immune responses. During the last 80 years many adjuvants have been used in experimental settings, but due to various shortcomings of most of them only aluminum compounds made it into regular clinical usage. However, during the last years promising candidates have arisen that may finally adjunct or displace aluminum substances as main adjuvant. This review summarizes information on adjuvants currently used in clinical as well as in experimental settings.

Gender-medicine aspects in allergology.

Despite the identical immunological mechanisms activating the release of mediators and consecutive symptoms in immediate‐type allergy, there is still a clear clinical difference between female and male allergic patients. Even though the risk of being allergic is greater for boys in childhood, almost from adolescence onwards it seems to be a clear disadvantage to be a woman as far as atopic disorders are concerned. Asthma, food allergies and anaphylaxis are more frequently diagnosed in females. In turn, asthma and hay fever are associated with irregular menstruation. Pointing towards a role of sex hormones, an association of asthma and intake of contraceptives, and a risk for asthma exacerbations during pregnancy have been observed. Moreover, peri‐ and postmenopausal women were reported to increasingly suffer from asthma, wheeze and hay fever, being even enhanced by hormone replacement therapy. This may be on account of the recently identified oestradiol‐receptor‐dependent mast‐cell activation. As a paradox of nature, women may even become hypersensitive against their own sex hormones, resulting in positive reactivity upon intradermal injection of oestrogen or progesterone. More importantly, this specific hypersensitivity is associated with recurrent miscarriages. Even though there is a striking gender‐specific bias in IgE‐mediated allergic diseases, public awareness of this fact still remains minimal today.

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.

Allergen‐loaded biodegradable poly(d,l‐lactic‐co‐glycolic) acid nanoparticles down‐regulate an ongoing Th2 response in the BALB/c mouse model

Background and objective Biocompatible and biodegradable microparticles have gained interest as antigen delivery systems during the recent years. We investigated whether biodegradable poly(d,l‐lactic‐co‐glycolic) acid (PLGA) nanospheres could be used as allergen vehicles for few‐shot therapy of type I allergy.