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Food Allergies: The Basics

  • Rudolf Valenta
    Correspondence
    Reprint requests Address requests for reprints to: Rudolf Valenta, MD, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. fax: (43) 1-40400-51300.
    Affiliations
    Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Heidrun Hochwallner
    Affiliations
    Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Birgit Linhart
    Affiliations
    Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Sandra Pahr
    Affiliations
    Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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Open AccessPublished:February 10, 2015DOI:https://doi.org/10.1053/j.gastro.2015.02.006
      IgE-associated food allergy affects approximately 3% of the population and has severe effects on the daily life of patients—manifestations occur not only in the gastrointestinal tract but also affect other organ systems. Birth cohort studies have shown that allergic sensitization to food allergens develops early in childhood. Mechanisms of pathogenesis include cross-linking of mast cell– and basophil-bound IgE and immediate release of inflammatory mediators, as well as late-phase and chronic allergic inflammation, resulting from T-cell, basophil, and eosinophil activation. Researchers have begun to characterize the molecular features of food allergens and have developed chip-based assays for multiple allergens. These have provided information about cross-reactivity among different sources of food allergens, identified disease-causing food allergens, and helped us to estimate the severity and types of allergic reactions in patients. Importantly, learning about the structure of disease-causing food allergens has allowed researchers to engineer synthetic and recombinant vaccines.

      Keywords

      Abbreviations used in this paper:

      FcεRI (Fc epsilon receptor I), IL (interleukin), OAS (oral allergy syndrome), SIgA (secretory IgA), SIT (specific immunotherapy), Th (T-helper)
      There are several mechanisms by which people develop adverse reactions to foods also termed food intolerance.
      • Metcalfe D.D.
      • Sampson H.A.
      • Simon R.A.
      Food allergy: adverse reactions to foods and food additives.
      These reactions can be considered toxic or nontoxic (Figure 1).
      • Bischoff S.C.
      • Sellge G.
      Immune mechanisms in food-induced disease.
      Among the nontoxic reactions, those that are not immune-mediated, such as those involving enzyme defects (eg, vasoactive amines) or reactions to certain substances (eg lactose intolerance), are far more common than immune-mediated reactions.
      • Bischoff S.C.
      • Sellge G.
      Immune mechanisms in food-induced disease.
      Nevertheless, immune-mediated reactions affect millions of people, are responsible for significant morbidity and health care costs, and can cause severe life-threatening reactions that lead to death.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      Food allergy was defined by an expert panel of the National Institute of Allergy and Infectious Diseases as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” This response comprises basically all types of immune-mediated reactions, including those caused by the adaptive and innate immune system (Figure 1).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      Figure thumbnail gr1
      Figure 1Classification of food intolerance. Adverse reactions to food can be classified as toxic or nontoxic reactions. Nontoxic reactions are categorized further as immune-mediated or non–immune-mediated. The most common adverse reactions are based on non–immune-mediated mechanisms such as enzyme defects as observed in lactose intolerance. Hypersensitivities involving the adaptive immune system can be subdivided into 4 categories (types I–IV). Type I reactions are always associated with the formation of IgE against food allergens and therefore can be called IgE-associated food allergies. There is firm evidence for an involvement of IgG in type II or type III reactions in immune-mediated adverse reactions to food, whereas type IV reactions, which involve T cells, have important roles in disorders such as celiac disease. There is evidence that the innate immune system, which includes complement, Toll-like receptors, and innate immune cells, also mediates immune reactions against certain food components.
      The term allergy was coined in 1906 by the Austrian pediatrician Clemens von Pirquet,
      • Von Pirquet C.
      Allergie.
      who described cases of serum sickness in children treated with antibody preparations. According to Coombs and Gell,
      • Coombs R.R.A.
      • Gell P.G.H.
      Classification of allergic reactions responsible for clinical hypersensitivity and disease.
      there are 4 major types of allergic reactions based on pathogenesis mechanisms. The most common forms of immune-mediated adverse reactions to foods (type I reactions) always are characterized by the development of IgE against food allergens. It can be accompanied by inflammation, induced by cellular components, and mediated by T cells and eosinophils. Patients with IgE-associated food allergy can be identified based on the detection of food allergen–specific IgE in serum and body fluids, and by measuring IgE-mediated cellular and in vivo responses.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      Although it is tempting to speculate that food antigen–specific IgG can cause adverse reactions via type II or type III hypersensitivity, there is no solid experimental evidence to support the relevance of these reactions to food allergies that develop in patients (Figure 1). Accordingly, several position papers strongly recommend against testing for food antigen–specific IgG in the diagnosis of food allergy.
      • Stapel S.O.
      • Asero R.
      • Ballmer-Weber B.K.
      • et al.
      Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report.
      • Bock S.A.
      AAAAI support of the EAACI position paper on IgG4.
      Type IV hypersensitivity, which mainly involves food antigen–specific T-cell responses and can damage the gut mucosa, is associated with disorders such as celiac disease. Celiac disease is characterized by a hypersensitivity reaction against the wheat gluten fraction comprising alcohol soluble gliadins and acid-, alkali-soluble glutenins, accompanied by an autoimmune component.
      • Schuppan D.
      • Junker Y.
      • Barisani D.
      Celiac disease: from pathogenesis to novel therapies.
      Type IV hypersensitivity reactions also might be involved in food protein–induced enterocolitis (Figure 1).
      • Caubet J.C.
      • Ford L.S.
      • Sickles L.
      • et al.
      Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience.
      Studies have shown that certain food proteins can induce inflammation via direct activation of the innate immune system. For example, wheat amylase trypsin inhibitors and certain milk oligosaccharides can cause intestinal inflammation via activation of Toll-like receptor 4,
      • Junker Y.
      • Zeissig S.
      • Kim S.J.
      • et al.
      Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
      • Kurakevich E.
      • Hennet T.
      • Hausmann M.
      • et al.
      Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c+ cells through TLR4.
      and certain allergens have been shown to stimulate the innate immune system.
      • Ruiter B.
      • Shreffler W.G.
      Innate immunostimulatory properties of allergens and their relevance to food allergy.
      Innate immune mechanisms might mediate nonceliac gluten sensitivity.
      • Catassi C.
      • Bai J.C.
      • Bonaz B.
      • et al.
      Non-celiac gluten sensitivity: the new frontier of gluten related disorders.
      In developed countries, IgE-associated food allergy affects 3%–8% of children and 1%–3% of adults.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      It not only is common, but often is a serious and life-threatening health condition that requires accurate diagnosis and has strong effects on an individual’s dietary habits and social life. Milk, eggs, wheat, peanuts, nuts, sesame, fish, fruits, and vegetables are common inducers of IgE-associated food allergy.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      Allergies to foods such as milk, egg, and wheat often are outgrown (patients acquire tolerance), whereas allergies to peanuts, tree nuts, and fish allergies often persists over a lifetime.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      The exact incidence of food allergies has not been fully established because there are discrepancies among findings from studies in which food allergies were self-reported vs those diagnosed by various assays (eg, provocation, skin test, or serologic tests).
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      • Burney P.G.
      • Potts J.
      • Kummeling I.
      • et al.
      The prevalence and distribution of food sensitization in European adults.
      The prevalence and severity of food allergies seem to be increasing. In addition to genetic factors, a number of environmental, cultural, and behavioral factors affect the frequency, severity, and type of allergic manifestations in patients.
      • Lack G.
      Update on risk factors for food allergy.
      • Gray C.L.
      • Levin M.E.
      • Zar H.J.
      • et al.
      Food allergy in South African children with atopic dermatitis.
      • Baumann S.
      • Lorentz A.
      Obesity-a promoter of allergy?.
      • Marrs T.
      • Bruce K.D.
      • Logan K.
      • et al.
      Is there an association between microbial exposure and food allergy? A systematic review.
      A recent study identified epigenetic differences in CD4+ T cells from children with IgE-mediated food allergies, compared with children without food allergies—differences such as these might contribute to the development of a food allergy.
      • Martino D.
      • Joo J.E.
      • Sexton-Oates A.
      • et al.
      Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy.
      According to the hygiene hypothesis, decreases in family size and improvements in personal hygiene have contributed to the increased prevalence of IgE-mediated allergies. On the other hand, factors such as an anthroposophic lifestyle (eating organic foods that contain lactobacilli and restrictive use of antibiotics, antipyretics, and vaccines) have been associated with a reduced incidence of allergies.
      • Strachan D.P.
      Hay fever, hygiene, and household size.
      • Alm J.S.
      • Swartz J.
      • Björkstén B.
      • et al.
      An anthroposophic lifestyle and intestinal microflora in infancy.
      It has been proposed that insufficient exposure to dietary and bacterial metabolites might have contributed to increases in inflammatory disorders in Western countries.
      • Thorburn A.N.
      • Macia L.
      • Mackay C.R.
      Diet, metabolites, and “Western-lifestyle” inflammatory diseases.

      Allergic Sensitization and Secondary Immune Responses

      The term allergic sensitization describes the first induction of an allergic immune response upon allergen encounter.
      • Valenta R.
      The future of antigen-specific immunotherapy of allergy.
      • Valenta R.
      • Ball T.
      • Focke M.
      • et al.
      Immunotherapy of allergic disease.
      Two routes of allergic sensitization are well established (Figure 2A). Class 1 food allergens (eg, milk, egg, or peanut) are oral allergens that cause sensitization via the gastrointestinal tract.
      • Han Y.
      • Kim J.
      • Ahn K.
      Food allergy.
      Class 2 food allergens are aeroallergens (eg, major birch pollen allergen Bet v 1) that cause sensitization via the respiratory tract. Immune responses against these allergens can cross-react with homologous food allergens (eg, major apple allergen Mal d 1) to cause symptoms.
      • Ortolani C.
      • Ispano M.
      • Pastorello E.
      • et al.
      The oral allergy syndrome.
      • Ebner C.
      • Birkner T.
      • Valenta R.
      • et al.
      Common epitopes of birch pollen and apples-studies by Western and Northern blot.
      • Valenta R.
      • Kraft D.
      Type 1 allergic reactions to plant-derived food: a consequence of primary sensitization to pollen allergens.
      Figure thumbnail gr2
      Figure 2Time course, pathogenesis, and manifestations of food allergies. IgE-associated food allergies appear to develop early in childhood. This process is termed allergic sensitization. (A) Allergen contact via the gastrointestinal tract, via the respiratory tract, and eventually via the skin induces IgE production (primary sensitization) in genetically predisposed individuals. Repeated allergen contact activates allergen-specific T cells and induces IgE responses during the secondary immune response. Factors that affect the epithelial barrier (red arrows) and the extent to which allergens are digested or degraded are important for primary sensitization and boosting of secondary immune responses. SIgA and T-regulatory cells may be important for exclusion of allergens from the intestinal lumen and induction of tolerance, respectively. (B) The balance between allergen-specific IgE and blocking IgG helps determine whether or not a patient will develop symptoms. Allergen avoidance could reduce levels of allergen-specific IgE to below the threshold for symptom induction (lower panel), whereas exposure could increase production of IgE, leading to symptoms (upper panel). If allergen exposure induces allergen-specific IgG, which blocks the interaction between the allergen and IgE, then symptoms might be reduced (middle panel). (C) Allergy symptoms are caused by repeated contact with the oral allergen, via the immediate allergic reaction (allergen-induced cross-linking of mast cell–bound IgE by allergen and then activation of allergen-specific T cells), and then by other inflammatory cells, such as eosinophils and basophils, during late-phase and chronic inflammation. Factors that affect the epithelial barrier and the extent of allergen degradation affect the amount of allergen intrusion and the magnitude and type of inflammation. After allergen ingestion, inflammation develops not only in the intestine, but in other organs, such as the skin, respiratory tract, and circulatory system (right). These allergens and allergen fragments are internalized and distributed throughout the body (left). MHC, major histocompatibility complex; T-reg, T-regulatory cell; TCR, T-cell receptor.
      It recently was proposed that people become sensitized to food allergens via skin contact, but there have been few studies of this process.
      • Lack G.
      Update on risk factors for food allergy.
      Interestingly, studies of animal models have indicated that epicutaneous sensitization leads to expansion of IgE-dependent intestinal mast cells and food-induced allergic reactions.
      • Bartnikas L.M.
      • Gurish M.F.
      • Burton O.T.
      • et al.
      Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis.
      • Noti M.
      • Kim B.S.
      • Siracusa M.C.
      • et al.
      Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.
      For an overview of food allergen sources that may cause sensitization via the respiratory tract and skin, see the article by Asero and Antonicelli.
      • Asero R.
      • Antonicelli L.
      Does sensitization to foods in adults occur always in the gut?.
      Determinants of allergic sensitization include features of the epithelial barrier, the allergen itself (whether allergens are stable and not degraded in the environment or gastrointestinal tract), nonallergenic components of the food matrix, and substances that act as adjuvants (Figure 2A).
      • Breiteneder H.
      • Mills E.N.
      Molecular properties of food allergens.
      For example, food allergens have been proposed to have greater stability during digestion than other molecules in food.
      • Astwood J.D.
      • Leach J.N.
      • Fuchs R.L.
      Stability of food allergens to digestion in vitro.
      Intrinsic factors (eg, genetic factors such as mutations in the filaggrin gene) and exogenous factors (eg, alcohol, anti-inflammatory drugs, pathogens, or stress) have been proposed to reduce the barrier function of the intestinal epithelium and facilitate sensitization.
      • Groschwitz K.R.
      • Hogan S.P.
      Intestinal barrier function: molecular regulation and disease pathogenesis.
      • Irvine A.D.
      • McLean W.H.
      • Leung D.Y.
      Filaggrin mutations associated with skin and allergic diseases.
      • Perrier C.
      • Corthésy B.
      Gut permeability and food allergies.
      On the other hand, secretory antibodies, particularly secretory IgA (SIgA), have important roles in reinforcing the epithelial barrier. Mice deficient in SIgA and secretory IgM are prone to develop food allergen–induced anaphylactic shock, which can be overcome by induction of tolerance with T-regulatory cells.
      • Johansen F.E.
      • Pekna M.
      • Norderhaug I.N.
      • et al.
      Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice.
      • Karlsson M.R.
      • Johansen F.E.
      • Kahu H.
      • et al.
      Hypersensitivity and oral tolerance in the absence of a secretory immune system.
      Many environmental and genetic factors contribute to the atopic predisposition of individuals. These determine their susceptibility to develop allergic immune responses against allergens.
      • Grammatikos A.P.
      The genetic and environmental basis of atopic diseases.
      In atopic individuals who have a predisposition toward developing IgE-associated allergies, encounters with allergen activate, after processing by antigen-presenting cells (eg, dendritic cells or B cells), allergen-specific T-helper 2 (Th2) cells, which produce cytokines such as interleukin (IL)4 and IL13. These cytokines induce class switching and production of allergen-specific IgE.
      • Paul W.E.
      Interleukin 4/B cell stimulatory factor 1: one lymphokine, many functions.
      • Romagnani S.
      The Th1/Th2 paradigm.
      • Vercelli D.
      • Geha R.S.
      Regulation of isotype switching.
      Primary allergic sensitization (such as a class switch toward IgE production) occurs early in life and leads to T-cell and IgE memory, which can be boosted with repeated allergen contact (secondary immune response).
      • Henderson L.L.
      • Larson J.B.
      • Gleich G.J.
      Maximal rise in IgE antibody following ragweed pollination season.
      • Naclerio R.M.
      • Adkinson Jr., N.F.
      • Moylan B.
      • et al.
      Nasal provocation with allergen induces a secondary serum IgE antibody response.
      • Niederberger V.
      • Ring J.
      • Rakoski J.
      • et al.
      Antigens drive memory IgE responses in human allergy via the nasal mucosa.
      • Mojtabavi N.
      • Dekan G.
      • Stingl G.
      • et al.
      Long-lived Th2 memory in experimental allergic asthma.
      Upon contact with a primary food allergen, nonallergic individuals produce allergen-specific IgG and IgA, which do not induce allergic reactions. The formation of food allergen–specific IgE is a main feature of IgE-associated food allergy and its diagnosis.
      Analyses of the time courses of allergic sensitization to respiratory and food allergen sources in large birth cohort studies have shown that food allergies and their associated symptoms develop before respiratory allergies.
      • Kulig M.
      • Bergmann R.
      • Klettke U.
      • et al.
      Natural course of sensitization to food and inhalant allergens during the first 6 years of life.
      In later life, there is a reverse trend—food allergies often are outgrown and respiratory allergies increase and dominate.
      • Kulig M.
      • Bergmann R.
      • Klettke U.
      • et al.
      Natural course of sensitization to food and inhalant allergens during the first 6 years of life.
      Interestingly, the prevalence of food allergies is approximately 10-fold lower than that of respiratory allergies.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      • Katelaris C.H.
      • Lee B.W.
      • Potter P.C.
      • et al.
      Prevalence and diversity of allergic rhinitis in regions of the world beyond Europe and North America.
      This could be because oral exposure to allergens activates tolerance mechanisms (via regulatory T cells) and less frequently results in allergic sensitization than respiratory exposure to allergens.
      • Strobel S.
      • Mowat A.M.
      Oral tolerance and allergic responses to food proteins.
      • Chehade M.
      • Mayer L.
      Oral tolerance and its relation to food hypersensitivities.
      Several cellular mechanisms seem to influence primary allergic sensitization vs tolerance in the intestine. Tolerance can be mediated by antigen presentation by dendritic cells, which interact with C-type lectin receptors
      • Zhou Y.
      • Kawasaki H.
      • Hsu S.C.
      • et al.
      Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1.
      ; dendritic cell–bound IgE can down-regulate allergic inflammation at mucosal sites.
      • Platzer B.
      • Baker K.
      • Vera M.P.
      • et al.
      Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites.
      Children with an egg allergy were reported to have reduced function of neonatal T-regulatory cells compared with children without an egg allergy.
      • Smith M.
      • Tourigny M.R.
      • Noakes P.
      • et al.
      Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function.
      On the other hand, children who outgrew a cow’s milk allergy had increased T-regulatory cell responses.
      • Karlsson M.R.
      • Rugtveit J.
      • Brandtzaeg P.
      Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy.
      These findings indicate that T-regulatory cells modulate the development of food allergies.
      • Brandtzaeg P.
      Food allergy: separating the science from the mythology.
      After primary sensitization, the allergic immune response is boosted with repeated exposure to allergen, increasing activation of allergen-specific T cells and production of IgE.
      In persons with a respiratory allergy, the IgE response is boosted by contact with a mucosal allergen
      • Niederberger V.
      • Ring J.
      • Rakoski J.
      • et al.
      Antigens drive memory IgE responses in human allergy via the nasal mucosa.
      and, interestingly, does not seem to require T-cell help.
      • Egger C.
      • Horak F.
      • Vrtala S.
      • et al.
      Nasal application of rBet v 1 or non-IgE-reactive T-cell epitope-containing rBet v 1 fragments has different effects on systemic allergen-specific antibody responses.
      • Linhart B.
      • Bigenzahn S.
      • Hartl A.
      • et al.
      Costimulation blockade inhibits allergic sensitization but does not affect established allergy in a murine model of grass pollen allergy.
      • Marth K.
      • Wollmann E.
      • Gallerano D.
      • et al.
      Persistence of IgE-associated allergy and allergen-specific IgE despite CD4+ T cell loss in AIDS.
      Another interesting feature of the established secondary IgE response is that in adults with an allergy, the profile of allergens recognized by IgE does not change substantially, whereas it seems that young children can be sensitized to new allergens.
      • Lupinek C.
      • Marth K.
      • Niederberger V.
      • et al.
      Analysis of serum IgE reactivity profiles with microarrayed allergens indicates absence of de novo IgE sensitizations in adults.
      • Hatzler L.
      • Panetta V.
      • Lau S.
      • et al.
      Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever.
      In the case of a respiratory allergy, allergen contact through the respiratory mucosa strongly boosts IgE production, but has little influence on the other classes of allergen-specific antibodies (eg, IgA or IgG).
      • Niederberger V.
      • Ring J.
      • Rakoski J.
      • et al.
      Antigens drive memory IgE responses in human allergy via the nasal mucosa.
      The responding B ε memory cells may reside in the respiratory mucosa or the adjacent lymphoid tissues,
      • Durham S.R.
      • Gould H.J.
      • Thienes C.P.
      • et al.
      Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid.
      but little is known about the precise location of the cells involved in secondary IgE responses in allergic patients.
      • Eckl-Dorna J.
      • Pree I.
      • Reisinger J.
      • et al.
      The majority of allergen-specific IgE in the blood of allergic patients does not originate from blood-derived B cells or plasma cells.
      The mechanisms by which food allergen–specific IgE responses are boosted in patients with food allergies are poorly understood. When food allergens were administered orally, patients had strong increases in the production of allergen-specific IgG, accompanied by an initial boost of IgE.
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Oral immunotherapy for treatment of egg allergy in children.
      • Nozawa A.
      • Okamoto Y.
      • Movérare R.
      • et al.
      Monitoring Ara h 1, 2 and 3-sIgE and sIgG4 antibodies in peanut allergic children receiving oral rush immunotherapy.
      • Sato S.
      • Yanagida N.
      • Ogura K.
      • et al.
      Clinical studies in oral allergen-specific immunotherapy: differences among allergens.
      These findings indicated that allergen ingestion can boost allergen-specific production of IgG as well as IgE. It is possible that oral allergens can boost production of disease-causing IgE, as well as that of potentially protective IgG; this might explain why elimination or continued intake of food allergens can benefit patients.
      • Prescott S.L.
      • Bouygue G.R.
      • Videky D.
      • et al.
      Avoidance or exposure to foods in prevention and treatment of food allergy?.
      • Fisher H.R.
      • du Toit G.
      • Lack G.
      Specific oral tolerance induction in food allergic children: is oral desensitisation more effective than allergen avoidance?: a meta-analysis of published RCTs.
      It is clear that avoidance of food allergens over a prolonged period of time reduces levels of allergen-specific IgE below the threshold level for symptoms (Figure 2B). However, there is controversy about whether intake of food allergens is beneficial. If food allergen intake mainly stimulates production of protective IgG antibodies, tolerance could be induced and allergen-specific IgE production could be reduced. However, insufficient IgG production could cause IgE levels to increase, leading to increased sensitivity and symptoms (Figure 2B). Several recent studies have shown that the induction of allergen-specific IgG antibodies, which block IgE recognition of food allergens, is associated with the successful immunotherapy for food allergy.
      • Sato S.
      • Yanagida N.
      • Ogura K.
      • et al.
      Clinical studies in oral allergen-specific immunotherapy: differences among allergens.

      Pathogenesis and Manifestations of Food Allergy

      Upon interaction with food antigens, IgE becomes cross-linked and binds to mast cells and basophils via the high-affinity receptor FcεRI (Figure 2C).
      • Bischoff S.
      • Crowe S.E.
      Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives.
      This process activates these cells, leading to the release of granules that contain preformed inflammatory mediators (eg, histamine), as well as de novo synthesis and/or release of inflammatory mediators (eg, leukotrienes), proteases (eg, tryptase), inflammatory cytokines (eg, IL4), and chemotactic molecules. Mast cells and basophils are activated within a few minutes of IgE cross-linking, therefore this process it called an immediate allergic reaction; symptoms occur shortly after allergen contact.
      Because food allergens enter the blood via the gastrointestinal tract, symptoms can develop directly at the sites of allergen contact (eg, mouth, esophagus, and/or intestine), or in other organs. Systemic reactions occur when allergens capable of cross-linking effector cell-bound IgE pass the barrier of the mucosa into the circulation (Figure 2C, right). Allergen uptake also may affect the circulatory and nervous systems.
      Factors that contribute to the type and severity of reactions include the amount of ingested allergen, the stability of the allergen against digestion, and the permeability of the epithelial barrier (Figure 2C). The immediate allergic reaction leads to intense inflammation that can become life-threatening. The release of vasoactive mediators into the circulation can lead to vascular collapse and anaphylactic shock.
      • Worm M.
      • Eckermann O.
      • Dölle S.
      • et al.
      Triggers and treatment of anaphylaxis: an analysis of 4,000 cases from Germany, Austria and Switzerland.
      Supplementary Table 1 summarizes the clinical manifestations of food allergies, the organ systems affected by IgE-mediated mast cell and basophil degranulation, and the clinical aspects of gastrointestinal food allergy.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      Studies performed with well-defined reagents (eg, monoclonal IgE, in vitro cellular systems, defined allergens, and IgE epitopes) have shown that the degranulation of effector cells, and therefore the intensity of the immediate-type reaction, increases with the number of IgE epitopes on an allergen, high levels of allergen-specific IgE, and high-affinity allergen-specific IgE.
      • Gieras A.
      • Focke-Tejkl M.
      • Ball T.
      • et al.
      Molecular determinants of allergen-induced effector cell degranulation.
      • Christensen L.H.
      • Holm J.
      • Lund G.
      • et al.
      Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge.
      • Dema B.
      • Suzuki R.
      • Rivera J.
      Rethinking the role of immunoglobulin E and its high-affinity receptor: new insights into allergy and beyond.
      The fact that high levels of allergen-specific IgE cause up-regulation of FcεRI on mast cells and basophils, and thereby a more dense loading of these cells with IgE, could account for the association between levels of allergen-specific IgE against stable food allergens and the severity of allergic reactions.
      • MacGlashan Jr., D.
      • Lichtenstein L.M.
      • McKenzie-White J.
      • et al.
      Upregulation of FcepsilonRI on human basophils by IgE antibody is mediated by interaction of IgE with FcepsilonRI.
      • Yamaguchi M.
      • Sayama K.
      • Yano K.
      • et al.
      IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release.
      • Yunginger J.W.
      • Ahlstedt S.
      • Eggleston P.A.
      • et al.
      Quantitative IgE antibody assays in allergic diseases.
      In addition to the levels of FcεRI on mast cells, the number of intestinal mast cells and basophils and (probably related to mast cell numbers and activation) the levels of intestinal tryptase also seem to be related to the severity of reactions to food allergens.
      • Ahrens R.
      • Osterfeld H.
      • Wu D.
      • et al.
      Intestinal mast cell levels control severity of oral antigen-induced anaphylaxis in mice.
      • Reber L.L.
      • Marichal T.
      • Mukai K.
      • et al.
      Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice.
      • Hagel A.F.
      • deRossi T.
      • Zopf Y.
      • et al.
      Mast cell tryptase levels in gut mucosa in patients with gastrointestinal symptoms caused by food allergy.
      Interestingly, studies performed in animal models have shown that cytokines such as IL4 can induce expansion of intestinal mast cells.
      • Burton O.T.
      • Darling A.R.
      • Zhou J.S.
      • et al.
      Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.
      In addition to the immediate allergic reaction (the most frequent pathogenic mechanism of IgE-associated allergies), late-phase allergic reactions also occur after allergen contact; there are 2 types. The late-phase response to allergens has been studied in mainly cutaneous models, such as skin blister and skin chamber models. Several hours after allergen contact and the immediate reaction, there is an influx of basophils and eosinophils.
      • Charlesworth E.N.
      • Hood A.F.
      • Soter N.A.
      • et al.
      Cutaneous late-phase response to allergen. Mediator release and inflammatory cell infiltration.
      This influx is steroid-sensitive and seems to involve granulocyte-macrophage colony-stimulating factor.
      • Charlesworth E.N.
      • Kagey-Sobotka A.
      • Schleimer R.P.
      • et al.
      Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen.
      Relatively little is known about the importance of late-phase reactions in food allergy, but it is tempting to speculate that they could be involved in food allergen–induced forms of eosinophilic gastroenteritis.
      • Rothenberg M.E.
      Biology and treatment of eosinophilic esophagitis.
      In fact, data from experimental animal models have indicated that thymic stromal lymphopoetin–induced basophil responses promote eosinophilic esophagitis.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      Interestingly, it also has been shown that enteric eosinophils not only contribute to inflammation, but control dendritic cells to initiate primary Th2 cell–mediated immune responses, indicating a complex interaction among cells in food allergies.
      • Chu D.K.
      • Jimenez-Saiz R.
      • Verschoor C.P.
      • et al.
      Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.
      In addition to the late-phase responses, delayed-type reactions can occur 24–48 hours after allergen contact. These resemble features of a type IV hypersensitivity reaction, involving allergen-specific T cells. Allergen-specific T cells can be activated via IgE-dependent and IgE-independent pathways (Figure 2). In fact, in patients with allergies, antigen-presenting cells express FcεRI as well as the low-affinity receptor for IgE (FcεRII also known as CD23). The cells use this receptor for IgE-facilitated allergen presentation—a process found to be more effective for T-cell activation than allergen presentation without IgE.
      • Novak N.
      • Bieber T.
      • Kraft S.
      Immunoglobulin E-bearing antigen-presenting cells in atopic dermatitis.
      • van Neerven R.J.
      • Knol E.F.
      • Ejrnaes A.
      • et al.
      IgE-mediated allergen presentation and blocking antibodies: regulation of T-cell activation in allergy.
      Studies performed with allergen peptides that do not react with IgE and recombinant allergen derivatives showed that activation of allergen-specific T cells also can occur without IgE, and lead to delayed-type allergic reactions in patients.
      • Haselden B.M.
      • Kay A.B.
      • Larché M.
      Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions.
      • Campana R.
      • Mothes N.
      • Rauter I.
      • et al.
      Non-IgE-mediated chronic allergic skin inflammation revealed with rBet v 1 fragments.
      Induction of atopic dermatitis by food allergens has been shown to require not only Th2 cells (and Th2 cytokines such as IL4, IL13, and IL5—a cytokine that activates eosinophils), but also Th1 cells, which mediated delayed allergic inflammation.
      • Reekers R.
      • Beyer K.
      • Niggemann B.
      • et al.
      The role of circulating food antigen-specific lymphocytes in food allergic children with atopic dermatitis.
      Interferon-γ, secreted by allergen-specific Th1 cells, was shown to induce epithelial damage in a model of respiratory allergy.
      • Reisinger J.
      • Triendl A.
      • Küchler E.
      • et al.
      IFN-gamma-enhanced allergen penetration across respiratory epithelium augments allergic inflammation.
      The immediate- and delayed-type allergic inflammation that occurs during IgE-associated food allergy has been studied extensively in patients with oral allergy syndrome (OAS) (Supplementary Table 1). OAS is caused by sensitization to respiratory allergens that structurally are similar to allergens in foods, leading to a cross-reactive immune response. The most common form of OAS develops with sensitization to the major birch pollen allergen, Bet v 1. In patients with this form of OAS, the immune response cross-reacts with allergens in plant-derived food such as apples, nuts, carrots, and celery.
      • Ebner C.
      • Hirschwehr R.
      • Bauer L.
      • et al.
      Identification of allergens in fruits and vegetables: IgE cross-reactivities with the important birch pollen allergens Bet v 1 and Bet v 2 (birch profilin).
      This leads to local allergy symptoms of the immediate type (local itching and swelling of the lips or tongue), caused by IgE-mediated mast cell degranulation.
      • Kazemi-Shirazi L.
      • Pauli G.
      • Purohit A.
      • et al.
      Quantitative IgE inhibition experiments with purified recombinant allergens indicate pollen-derived allergens as the sensitizing agents responsible for many forms of plant food allergy.
      However, Bet v 1–related plant food allergens are digested by the gastrointestinal tract, therefore systemic reactions occur only in exceptional cases (such as after consumption of large amounts of the plant food allergens during exercise), and anaphylactic shock does not occur.
      • Kleine-Tebbe J.
      • Vogel L.
      • Crowell D.N.
      • et al.
      Severe oral allergy syndrome and anaphylactic reactions caused by a Bet v 1- related PR-10 protein in soybean, SAM22.
      Likewise, cooking destroys IgEs, but leaves peptides recognized by allergen-specific T cells intact.
      • Bohle B.
      • Zwölfer B.
      • Heratizadeh A.
      • et al.
      Cooking birch pollen-related food: divergent consequences for IgE- and T cell-mediated reactivity in vitro and in vivo.
      Ingestion of Bet v 1–related plant food allergens therefore can activate allergen-specific T cells by IgE-independent mechanisms, and induce late-phase and chronic allergic inflammation to cause disorders such as atopic dermatitis in sensitized patients.
      • Reekers R.
      • Busche M.
      • Wittmann M.
      • et al.
      Birch pollen-related foods trigger atopic dermatitis in patients with specific cutaneous T-cell responses to birch pollen antigens.
      Information on the time until onset of allergic reactions after food allergen intake (minutes–hours vs hours–days) and allergy phenotype (eg, urticaria vs atopic dermatitis) can help to determine whether the symptoms involve immediate IgE-mediated mast cell or basophil activation, or late-phase or chronic allergic inflammation caused by T-cell or eosinophil activation. Then, it is possible to select the most appropriate therapy. For example, immediate reactions would be treated with antihistamines, antileukotrienes, epinephrine, mast cell stabilizers, or anti-IgE, whereas late-phase chronic inflammation would be treated with steroids or anti-IL5.

      Preventing Food Allergies

      According to the current food allergy and anaphylaxis guidelines of the European Academy of Allergy and Clinical Immunology,
      • Muraro A.
      • Werfel T.
      • Hoffmann-Sommergruber K.
      • et al.
      EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.
      there are no restrictions regarding diet for mothers during pregnancy and lactation. Exclusive breastfeeding is recommended for the first 4–6 months of life, which prevents the development of allergies. If breastfeeding is not possible, hypoallergenic formulas with documented preventive effects are recommended for high-risk children. Breastfeeding transfers protective SIgA to the child, which may prevent allergic sensitization, and avoids early exposure to potential food allergens. This process may involve the uptake of SIgA-allergen complexes via receptors on M cells. Although certain studies have shown that early feeding of probiotics can reduce the development of allergic manifestations, particularly eczema, other studies have found that probiotic supplementation during early childhood did not prevent the development of allergic diseases.
      • Nermes M.
      • Salminen S.
      • Isolauri E.
      Is there a role for probiotics in the prevention or treatment of food allergy?.
      • Bertelsen R.J.
      • Brantsaeter A.L.
      • Magnus M.C.
      • et al.
      Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases.
      Likewise, there is no clear evidence that the administration of prebiotics or lipopolysaccharides can prevent the development of allergies.
      • Osborn D.A.
      • Sinn J.K.
      Prebiotics in infants for prevention of allergy.
      Accordingly, there is currently no evidence to support the use of prebiotics or probiotics in the prevention of food allergies. However, research is underway to identify specific probiotics or prebiotics that affect allergy development.
      • Muraro A.
      • Werfel T.
      • Hoffmann-Sommergruber K.
      • et al.
      EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.

      Diagnosis and Management

      Once a patient is diagnosed with a food allergy, it becomes important to identify the allergen(s) that cause the disorder and determine if it is mediated by IgE. If so, treatments for IgE-associated allergies can be selected (Figure 3). In early studies of food allergies,
      • Rowe A.H.
      Abdominal food allergy: its history, symptomatology, diagnosis and treatment.
      diagnoses were based on careful analyses of case histories and diaries to document symptoms and offending foods.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      For more information on the diagnosis of food allergies, see Figure 3 and articles by Sicherer and Sampson,
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      De Silva et al,
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      and Boyce et al.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      Figure thumbnail gr3
      Figure 3Diagnosis and management of IgE-associated food allergies. The diagnosis of a food allergy involves a case history and a demonstration of allergen-specific IgE production. Provocation tests and diets are used to identify disease-causing allergens. Based on this information, allergen-specific forms of treatment can be selected. This approach currently is being introduced into clinical practice. CFSE, carboxyfluorescein succinimidyl ester; ELISA, enzyme-linked immunosorbent assay; RBL, rat basophilic leukemia.
      Results from serologic and in vitro tests alone are not sufficient for the diagnosis of IgE-associated food allergies because the presence of allergen-specific IgE is not always associated with symptoms.
      • Lieberman J.A.
      • Sicherer S.H.
      Diagnosis of food allergy: epicutaneous skin tests, in vitro tests, and oral food challenge.
      This might be because certain antigens in food react with IgE but do not have allergenic activity. Furthermore, certain allergens easily are degraded and/or do not pass the epithelial barrier in sufficient quantities. For this reason, provocation tests often are useful and required to confirm IgE-associated food allergy. Skin tests are relatively easy to perform, but just as for IgE tests, results are not always associated with symptoms. Skin tests can detect IgE-mediated mast cell degranulation; these include the skin-prick test, prick-to-prick test, and intradermal test. Atopy patch tests can detect delayed-type reactions mediated by T-cell reactions.
      Oral provocation tests are the most accurate in the diagnosis of clinically relevant IgE-associated food allergies once allergen-specific IgE has been detected. These involve placing patients on elimination diets, and re-introducing foods or providing an open oral challenge. A double-blind, placebo-controlled food challenge is the standard for antigen identification.
      • Gellerstedt M.
      • Bengtsson U.
      • Niggemann B.
      Methodological issues in the diagnostic work-up of food allergy: a real challenge.
      However, the double-blind, placebo-controlled food challenge can induce severe reactions and requires careful planning and well-equipped clinical facilities.
      Several provocation tests involve the application of mucosal allergens.
      • Kvenshagen B.K.
      • Jacobsen M.
      The value of mucosal allergen challenge for the diagnosis of food allergy.
      Major advances in the diagnosis of food allergies and identification of disease-causing allergens include new in vitro multiplex allergy tests, which involve purified allergens.
      IgE-associated food allergies are managed with allergen-specific treatments such as avoidance of the disease-causing allergens via diets that ensure balanced nutrition with the least possible effects on quality of life. The elimination diet is the most important and relevant long-term management strategy for food allergies.
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      Once the offending food allergens have been identified the allergenic food must be avoided. For a summary of the management paths and guidelines for treatment, see the articles by Sicherer and Sampson,
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      De Silva et al,
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      and Boyce et al.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      For patients with a cow’s milk allergy, milk can be replaced with extensively hydrolyzed milk formulas.
      • Fiocchi A.
      • Schünemann H.J.
      • Brozek J.
      • et al.
      Diagnosis and rationale for action against cow's milk allergy (DRACMA): a summary report.
      Allergen-specific immunotherapy (SIT) is currently the only allergen-specific and disease-modifying treatment that has long-term effects.
      • Larché M.
      • Akdis C.A.
      • Valenta R.
      Immunological mechanisms of allergen-specific immunotherapy.
      SIT is used mainly to treat respiratory allergies, and less frequently to treat food allergies because standardized vaccines are not available. In the case of food allergies, SIT often is performed orally, by administration of the offending food instead of a vaccine.
      • Sato S.
      • Yanagida N.
      • Ogura K.
      • et al.
      Clinical studies in oral allergen-specific immunotherapy: differences among allergens.
      • Edwards H.E.
      Oral desentitization in food allergy.
      Progress in the molecular characterization of food allergens will lead to the development of defined vaccines for the treatment of food allergies, as for respiratory allergens, which may become available in the future.
      • Valenta R.
      • Ferreira F.
      • Focke-Tejkl M.
      • et al.
      From allergen genes to allergy vaccines.
      • Linhart B.
      • Valenta R.
      Vaccines for allergy.
      • Zuidmeer-Jongejan L.
      • Fernandez-Rivas M.
      • Poulsen L.K.
      • et al.
      FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies.
      Patients diagnosed with IgE-mediated food allergies can be given medications to reduce their symptoms.
      • Longo G.
      • Berti I.
      • Burks A.W.
      • et al.
      IgE-mediated food allergy in children.
      • De Silva D.
      • Geromi M.
      • Panesar S.S.
      • et al.
      Acute and long-term management of food allergy: systematic review.
      These can be selected based on the involvement of IgE-mediated mast cell or basophil degranulation (antihistamines, antileukotrienes, epinephrine, anti-IgE), or T cells or eosinophil activation (steroids, anti-IL5) (Figure 3).
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
      This procedure is beginning to enter clinical practice.

      Food Allergen Structure, Pathogenesis, and Diagnosis

      Since the 1980s, we have learned much about the structure and immunologic characteristics of allergens, and the clinical reactions they can cause.
      • Valenta R.
      • Ferreira F.
      • Focke-Tejkl M.
      • et al.
      From allergen genes to allergy vaccines.
      Researchers have produced recombinant allergens comprising repertoires of the most common antigens. Instead of ill-defined allergen extracts, which are prepared from the allergen sources (eg, wheat, apple, milk, or peanuts) (Figure 4) and consist of mixtures of various allergens and nonallergenic materials, pure allergen molecules are available for diagnosis and allergen-specific therapy. Purified recombinant allergens can be used to determine a patient’s IgE reactivity profile.
      Figure thumbnail gr4
      Figure 4Component-resolved diagnosis of a food allergy. Different sources of food allergens contain several allergenic molecules (components); these can be produced as recombinant proteins or purified from natural sources. These allergens can be classified into IgE-reactive components (green), which are poor activators of inflammatory cells and therefore induce little or no clinical reactions; components that induce mild or mainly local symptoms (yellow); and components that often are associated with severe and systemic allergic reactions (red). Microarray technology can be used to determine reactivity profiles of patients. This process can be used to identify individual allergens that cause disease and foods to which patients are most likely to respond. The severity of reactions also can be predicted.
      Many allergen sources contain antigens that have little or no clinical relevance because they are poor inducers of allergic reactions. These include IgE-reactive carbohydrate epitopes without allergenic activity,
      • Altmann F.
      The role of protein glycosylation in allergy.
      or molecules that induce only mild or local symptoms. Other molecules can induce severe systemic allergic reactions (Figure 4).
      Marker allergens have been identified from the most common food allergen sources (eg, apple, peanut, milk, and wheat).
      • Fernández-Rivas M.
      • Bolhaar S.
      • González-Mancebo E.
      • et al.
      Apple allergy across Europe: how allergen sensitization profiles determine the clinical expression of allergies to plant foods.
      • Vereda A.
      • van Hage M.
      • Ahlstedt S.
      • et al.
      Peanut allergy: clinical and immunologic differences among patients from 3 different geographic regions.
      • Amoah A.S.
      • Obeng B.B.
      • Larbi I.A.
      • et al.
      Peanut-specific IgE antibodies in asymptomatic Ghanaian children possibly caused by carbohydrate determinant cross-reactivity.
      • Hochwallner H.
      • Schulmeister U.
      • Swoboda I.
      • et al.
      Microarray and allergenic activity assessment of milk allergens.
      • Constantin C.
      • Quirce S.
      • Poorafshar M.
      • et al.
      Micro-arrayed wheat seed and grass pollen allergens for component-resolved diagnosis.
      Marker allergens are those found only in specific sources, and can be used to confirm sensitizations to these sources. Other allergens are present in different food sources. Patients who are sensitized to these can develop symptoms after ingestion of seemingly unrelated foods.
      Individual allergen molecules are named and listed by the nomenclature committee of the World Health Organization and International Union of Immunological Societies.
      • Radauer C.
      • Nandy A.
      • Ferreira F.
      • et al.
      Update of the WHO/IUIS Allergen Nomenclature Database based on analysis of allergen sequences.
      For an overview of the general biochemical characterization and features of allergens (see the article by Valenta
      • Valenta R.
      Biochemistry of allergens and recombinant allergens.
      ). Several databases also store information on allergens, including names, classifications, and characteristics (eg, http://www.allergen.org/; http://farrp.unl.edu/resources/farrp-databases; http://allergen.nihs.go.jp/ADFS/; http://www.allergome.org/; http://www.meduniwien.ac.at/allergens/allfam/; and http://www.allergenonline.org/).
      Table 1 shows some important plant food and animal food allergen families. According to a recent classification, allergens from different sources can be grouped into families with similar biologic functions, primary structure, and immunologic cross-reactivity.

      Breiteneder H, Mills C. Food allergens – molecular and immunological characteristics. In: Metcalfe DD, Sampson HA, Simon RA, et al, eds. Food allergy: adverse reactions to foods and food additives. 5th ed. Chichester, UK: John Wiley & Sons Ltd.

      A few examples for allergens from different sources that can be attributed to these structurally related allergen families are shown in Table 1.
      Table 1Plant Food and Animal Food Allergen Families.
      FamilyFunctionSelected allergens (names/sources)
      Plant food allergen families
       ProlaminsSeed storage proteinsSec c 20/Rye; Tri a 19/wheat; Tri a 36/wheat
       Nonspecific lipid transfer proteinsInvolved in lipid transport, plant defenseAct d 10/Kiwi; Api g 2/celery; Ara h 9/peanut;

      Cas s 8/chestnut; Cor a 8/hazelnut; Jug r 3/walnut;

      Lyc e 3/tomato; Mus a 3/banana; Pru du 3/almond;

      Pru p 3 /peach; Tri a 14/wheat; Zea m 14/maize
       2S albuminsSeed storage proteinsAna o 3/cashew nut; Ara h 2/peanut; Ber e 1/Brazil nut; Fag e 2/buckwheat; Gly m 8/soybean;

      Jug r 1/walnut; Ses i 1/sesame; Sin a 1/mustard
       Bet v 1 familyPathogenesis-related proteinsApi g 1/celery; Ara h 8/peanut; Cor a 1/hazelnut;

      Dau c 1/carrot; Gly m 4/soybean; Mal d 1/apple;

      Pru p 1/peach
      Cupin superfamily
       7S (vicilin-like) globulinsSeed storage proteinsAna o 1/cashew nut; Ara h 1/peanut;

      Gly m 5/soybean; Jug r 2/walnut; Pis v 3/pistachio
       11S (legumin-like) globulinsSeed storage proteinsAna o 2/cashew nut; Ara h 3/peanut; Ber e 2/Brazil nut; Cor a 9/hazelnut; Gly m 6/soybean;

      Jug r 4/walnut; Pru du 6/almond
       Cysteine protease C1 familyCysteine proteasesAct d 1/kiwi; Gly m Bd 30K/soybean
       ProfilinsActin-binding proteinsAct d 9/kiwi; Api g 4/celery; Ara h 5/peanut;

      Cuc m 2/melon; Dau c 4/carrot; Gly m 3/soybean;

      Lyc e 1/tomato; Mus a 1/banana; Ory s 12/rice;

      Pru av 4/cherry; Pru du 4/almond; Pru p 4/peach;

      Tri a 12/wheat
      Animal food allergen families
       Tropomyosin familyActin-binding proteins in musclePen m 1/shrimp
       Parvalbumin familyMuscle proteins, involved in muscle contractionCyp c 1/carp; Gad c 1/cod; Ran e 2/frog;

      Sal s 1/salmon; Seb m 1/redfish; Xip g 1/swordfish
       CaseinsMammalian milk proteins, form stable micellar complexesBos d 8–Bos d 12/cow’s milk
       Transferrin familySulfur-rich ion-binding glycoproteins from milk and hen’s egg whiteBos d Lactoferrin/cow’s milk; Gal d 3/hen’s egg
       SerpinsSerine protease inhibitorsGal d 2/hen’s egg
       Arginine kinasesAdenosine triphosphate: guanido phosphotransferasesPen m 2/shrimp
       LipocalinsCarrier proteinsBos d 5/cow’s milk
       Lysozyme familyEnzymatic activity, lactose synthesis in milkBos d 4/cow’s milk; Gal d 4/hen’s egg
       OvomucoidsKazal inhibitors, contain Kazal-type inhibitor repeatsGal d 1/hen’s egg
       AlbuminsSerum albumins, transport proteinsBos d 6/cow’s milk; Gal d 5/hen’s egg
      NOTE. Biologic functions of the proteins and selected allergens from various food allergen sources are named according to the International Union of Immunological Societies allergen nomenclature.
      The diagnosis of food and other allergies has transitioned from the identification of allergen sources without knowledge of the molecules that cause the symptoms, to the precise identification of allergy-inducing molecules. These processes are called “component-resolved allergy diagnosis” and “molecular allergy diagnosis.”
      • Canonica G.W.
      • Ansotegui I.J.
      • Pawankar R.
      • et al.
      A WAO - ARIA - GA2LEN consensus document on molecular-based allergy diagnostics.
      Our ability to test a patient’s reactivity to a growing number of well-characterized allergen molecules has required the development of new diagnostic tests. We now can test small volumes of serum for IgE reactivity against multiple allergens simultaneously. Allergen chips containing micro-arrayed allergen molecules have been developed for this purpose
      • Hiller R.
      • Laffer S.
      • Harwanegg C.
      • et al.
      Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment.
      ; they can be used to analyze serum samples for reactivity with a comprehensive set of molecules. This approach is ideal for analysis of children, or studies of differences or changes in allergic immune responses in large groups, such as birth cohorts.
      • Lupinek C.
      • Wollmann E.
      • Baar A.
      • et al.
      Advances in allergen-microarray technology for diagnosis and monitoring of allergy: the MeDALL allergen-chip.
      Based on component-resolved allergy diagnosis, the type and severity of symptoms can be predicted. Furthermore, the most relevant components can be identified to aid in the development of allergen-specific treatments and preventative strategies.
      • Valenta R.
      • Campana R.
      • Marth K.
      • et al.
      Allergen-specific immunotherapy: from therapeutic vaccines to prophylactic approaches.

      Allergen-Specific Prevention and Therapy

      A major limitation of SIT is the difficulty in preparation of effective and safe vaccines from natural allergen sources.
      • Focke M.
      • Swoboda I.
      • Marth K.
      • et al.
      Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity.
      However, based on the knowledge of the structure of the disease-causing allergens, it has become possible to produce new forms of allergy vaccines based on purified allergen molecules (Figure 5).
      • Valenta R.
      • Ferreira F.
      • Focke-Tejkl M.
      • et al.
      From allergen genes to allergy vaccines.
      Clinical trials have shown the efficacy of immunotherapies that include recombinant allergens in the wild-type, folded forms.
      • Valenta R.
      • Linhart B.
      • Swoboda I.
      • et al.
      Recombinant allergens for allergen-specific immunotherapy: 10 years anniversary of immunotherapy with recombinant allergens.
      Vaccines can be developed based on these allergens, under standardized conditions.
      Figure thumbnail gr5
      Figure 5Allergen-specific forms of prophylaxis and treatment. Multiplex allergen systems can be used to identify disease-relevant food allergens in populations. (A) Based on the mapping of antigen epitopes recognized by patients’ IgE and T cells, 4 molecular approaches are being developed for prophylaxis and treatment. These are as follows: recombinant wild-type allergens, carrier-bound B-cell epitope–containing peptides (which do not react with IgE, have reduced allergen-specific epitopes recognized by T cells, and induce allergen-specific IgG), recombinant hypoallergens (which have reduced reactivity with IgE and fewer epitopes that interact with T cells, and induce allergen-specific IgG), and peptide epitopes that interact with T cells (but do not react with IgE or induce allergen-specific IgG). (B) Allergen-specific treatment can be prophylactic (prenatal or early postnatal) or be given after sensitization has taken place (specific immunotherapy). Active vaccination, passive immunization with allergen-specific antibodies, and tolerance induction are options.
      However, wild-type allergens still contain epitopes that activate IgE and T cells, and therefore might induce allergic reactions in patients. Three approaches, based on modified allergens, have been developed to make allergy vaccines more safe, effective, and convenient. These allow for selective targeting of different facets of the allergic immune response. They include synthetic allergen-derived peptides that contain allergen-specific T-cell epitopes without IgE reactivity.
      • Larché M.
      T cell epitope-based allergy vaccines.
      Because of their small size, peptide vaccines can induce T-cell tolerance without allergen-specific IgG responses. Recombinant hypoallergenic allergen derivatives are characterized by strongly reduced IgE reactivity, and contain allergen-specific T-cell epitopes. After internalization, they can induce allergen-specific IgG responses.
      • Linhart B.
      • Valenta R.
      Mechanisms underlying allergy vaccination with recombinant hypoallergenic allergen derivatives.
      Carrier-bound peptides that contain B-cell epitopes are fusion proteins that consist of an allergen-unrelated carrier protein and nonallergenic peptides from the IgE binding sites of allergens. They lack IgE reactivity and most allergen-specific T-cell epitopes, but can induce allergen-specific IgG antibodies.
      • Focke-Tejkl M.
      • Valenta R.
      Safety of engineered allergen-specific immunotherapy vaccines.
      These approaches are in immunotherapy trials for patients with respiratory allergies. Results from clinical studies have indicated that the induction of allergen-specific IgG that blocks the interaction between allergens and IgE are necessary for immunotherapy of respiratory and food allergies.
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Oral immunotherapy for treatment of egg allergy in children.
      • Larché M.
      • Akdis C.A.
      • Valenta R.
      Immunological mechanisms of allergen-specific immunotherapy.
      It therefore is conceivable that food allergies can be treated in a similar manner as respiratory allergies—not only by oral SIT but also by vaccination protocols. In fact, a vaccine for fish allergies, based on a recombinant hypoallergenic derivative of the major fish allergen (Cyp c 1), is being evaluated in a phase 2 immunotherapy trial in a European Union–funded research program.
      • Zuidmeer-Jongejan L.
      • Fernandez-Rivas M.
      • Poulsen L.K.
      • et al.
      FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies.
      • Swoboda I.
      • Bugajska-Schretter A.
      • Linhart B.
      • et al.
      A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE-mediated fish allergy.
      • Swoboda I.
      • Balic N.
      • Klug C.
      • et al.
      A general strategy for the generation of hypoallergenic molecules for the immunotherapy of fish allergy.
      Food allergies also might be prevented with prenatal or early postnatal strategies to prevent allergic sensitization. Studies of animal models have shown that vaccination of pregnant mice with molecules that induce allergen-specific IgG, or administration of allergen-specific IgG, prevented allergic sensitization in offspring.
      • Uthoff H.
      • Spenner A.
      • Reckelkamm W.
      • et al.
      Critical role of preconceptional immunization for protective and nonpathological specific immunity in murine neonates.
      • Flicker S.
      • Gadermaier E.
      • Madritsch C.
      • et al.
      Passive immunization with allergen-specific antibodies.
      There is evidence that post-natal administration of hydrolyzed milk that contains allergen-derived peptides can induce tolerance.
      • von Berg A.
      • Filipiak-Pittroff B.
      • Krämer U.
      • et al.
      Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study.
      However, a recent study in which children at risk for celiac disease were given gluten as infants showed no effects.
      • Vriezinga S.L.
      • Auricchio R.
      • Bravi E.
      • et al.
      Randomized feeding intervention in infants at high risk for celiac disease.
      Research programs are underway to determine when and how best to expose infants to potential allergens (eg, peanut allergens) to avoid sensitization and/or induce tolerance.
      • Du Toit G.
      • Roberts G.
      • Sayre P.H.
      • et al.
      Identifying infants at high risk of peanut allergy: the Learning Early About Peanut Allergy (LEAP) screening study.
      In addition to prenatal approaches, strategies also might be developed to prevent allergy based on early vaccination or administration of allergen-specific IgG shortly after birth.
      • Flicker S.
      • Linhart B.
      • Wild C.
      • et al.
      Passive immunization with allergen-specific IgG antibodies for treatment and prevention of allergy.
      In addition to subcutaneous administration, immunotherapy for food allergy can be given by sublingual, oral, or epitcutaneous delivery.
      • Jones S.M.
      • Burks A.W.
      • Dupont C.
      State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.
      Sublingual therapy has been used for therapeutic vaccination but recently was found to be safe and induce tolerance in children with IgE sensitization but without allergic symptoms.
      • Szépfalusi Z.
      • Bannert C.
      • Ronceray L.
      • et al.
      Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects.
      Clinical studies of patients with egg or peanut allergies found that oral immunotherapy not only is effective for treatment,
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Oral immunotherapy for treatment of egg allergy in children.
      but also induces sustained protection, for up to 5 years.
      • Vickery B.P.
      • Scurlock A.M.
      • Kulis M.
      • et al.
      Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.
      Various forms of oral immunotherapy currently are used in different countries.
      We need to identify disease-relevant allergens as well as windows for early intervention if we are to develop preventive allergen-specific treatments. Studies are underway in birth cohorts. Because of the higher prevalence of respiratory allergies than food allergies, it is likely that first clinical prevention studies will be performed for respiratory allergens. However, findings should be applicable to food allergies.
      Specific immunotherapy of sensitized patients with recombinant and synthetic vaccines is most advanced for respiratory allergies, but approaches applied to respiratory allergens will be used to help develop defined vaccines for food allergy. Hypoallergenic allergen derivatives already have been made for several important food allergens and were evaluated in vitro and in animal models
      • Rancitelli P.
      • Hofmann A.
      • Burks A.W.
      Vaccine approaches for food allergy.
      ; a vaccine for fish allergies has been administered safely to patients in a clinical trial. We therefore can expect profound advances in sublingual immunotherapy for food allergies through recombinant allergen-based vaccines in the near future.

      Supplementary Material

      Supplementary Table 1Mechanisms and Clinical Manifestations of IgE-Associated Food allergy
      Organ systemClinical manifestationsImmunopathologyFeaturesAge and natural course
      SkinUrticaria, angioedema

      Flush, pruritus

      Oral allergy syndrome (local itching and tingling and/or edema of lips, tongue, palate and pharynx)
      IgE-mediated mast cell/basophil degranulationAcute onset after food ingestion (minutes-hours)In infants and adults, may resolve with age

      Appears mainly in adults with established pollen allergies, long-lived, boosted by pollen contact
      Contact urticariaAfter direct skin contactIn infants and adults
      Atopic dermatitis

      Protein contact dermatitis
      T cell-mediated (with or without involvement of IgE)Delayed type reaction > 24 hours after food ingestionIn infants and adults
      Respiratory tractLaryngeal and/or pharyngeal edema

      Hoarseness, cough
      IgE-mediated mast cell/basophil degranulationAcute onset after food ingestion (minutes-hours)In infants and adults
      Rhinoconjunctivitis

      Bronchial asthma
      T cell-mediated (with or without involvement of IgE)Delayed type reaction > 24 hours after food ingestionIn infants and adults

      Baker’s asthma in adults
      Gastrointestinal tractColitis

      Diarrhea

      Gastroenteritis

      Anorexia

      Nausea, vomiting

      Abdominal pain

      Flatulence

      Abdominal distension
      IgE-mediated mast cell/basophil degranulationAcute onset after food ingestion (minutes-hours)In infants and adults
      GastroenteritisT cell-mediated (with or without involvement of IgE)Delayed type reaction > 24 hours after food ingestion, increased pro-inflammatory cytokine responsesIn infants and adults, may resolve with age
      Eosinophilic gastroenteritis

      Eosinophilic esophagitis
      Eosinophilic gastroenteritisEosinophil-activation by cytokinesIn infants and adults
      Cardiovascular systemTachycardia

      Hypotension

      Vascular collapse

      Anaphylactic shock

      Cardiac dysrhythmia
      IgE-mediated mast cell/basophil degranulationAcute onset after food ingestion (minutes-hours)In infants and adults
      Nervous systemIrritability

      Anxiety
      IgE-mediated mast cell/basophil degranulation?Acute onset after food ingestion (minutes-hours)In infants and adults
      Confusionand/orand/or
      Loss of consciousnessT cell-mediated (with or without involvement of IgE)?Delayed type reaction > 24 hours after food ingestion

      References

        • Metcalfe D.D.
        • Sampson H.A.
        • Simon R.A.
        Food allergy: adverse reactions to foods and food additives.
        3rd ed. Blackwell Science, Malden, MA2003
        • Bischoff S.C.
        • Sellge G.
        Immune mechanisms in food-induced disease.
        in: 3rd ed. Food allergy: adverse reactions to foods and food additives. Blackwell Science, Malden, MA2003: 14-37
        • Sicherer S.H.
        • Sampson H.A.
        Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
        J Allergy Clin Immunol. 2014; 133: 291-307
        • Longo G.
        • Berti I.
        • Burks A.W.
        • et al.
        IgE-mediated food allergy in children.
        Lancet. 2013; 382: 1656-1664
        • De Silva D.
        • Geromi M.
        • Panesar S.S.
        • et al.
        Acute and long-term management of food allergy: systematic review.
        Allergy. 2014; 69: 159-167
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.
        J Allergy Clin Immunol. 2010; 126: 1105-1118
        • Von Pirquet C.
        Allergie.
        Mnch Med Wochenschrift. 1906; 30: 1457-1458
        • Coombs R.R.A.
        • Gell P.G.H.
        Classification of allergic reactions responsible for clinical hypersensitivity and disease.
        in: 3rd ed. Clin aspects immunol. Blackwell Scientific Publications, Oxford1975: 761-781
        • Stapel S.O.
        • Asero R.
        • Ballmer-Weber B.K.
        • et al.
        Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report.
        Allergy. 2008; 63: 793-796
        • Bock S.A.
        AAAAI support of the EAACI position paper on IgG4.
        J Allergy Clin Immunol. 2010; 125: 1410
        • Schuppan D.
        • Junker Y.
        • Barisani D.
        Celiac disease: from pathogenesis to novel therapies.
        Gastroenterology. 2009; 137: 1912-1933
        • Caubet J.C.
        • Ford L.S.
        • Sickles L.
        • et al.
        Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience.
        J Allergy Clin Immunol. 2014; 134: 382-389
        • Junker Y.
        • Zeissig S.
        • Kim S.J.
        • et al.
        Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
        J Exp Med. 2012; 209: 2395-2408
        • Kurakevich E.
        • Hennet T.
        • Hausmann M.
        • et al.
        Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c+ cells through TLR4.
        Proc Natl Acad Sci U S A. 2013; 110: 17444-17449
        • Ruiter B.
        • Shreffler W.G.
        Innate immunostimulatory properties of allergens and their relevance to food allergy.
        Semin Immunopathol. 2012; 34: 617-632
        • Catassi C.
        • Bai J.C.
        • Bonaz B.
        • et al.
        Non-celiac gluten sensitivity: the new frontier of gluten related disorders.
        Nutrients. 2013; 5: 3839-3853
        • Burney P.G.
        • Potts J.
        • Kummeling I.
        • et al.
        The prevalence and distribution of food sensitization in European adults.
        Allergy. 2014; 69: 365-371
        • Lack G.
        Update on risk factors for food allergy.
        J Allergy Clin Immunol. 2012; 129: 1187-1197
        • Gray C.L.
        • Levin M.E.
        • Zar H.J.
        • et al.
        Food allergy in South African children with atopic dermatitis.
        Pediatr Allergy Immunol. 2014; 25: 572-579
        • Baumann S.
        • Lorentz A.
        Obesity-a promoter of allergy?.
        Int Arch Allergy Immunol. 2013; 162: 205-213
        • Marrs T.
        • Bruce K.D.
        • Logan K.
        • et al.
        Is there an association between microbial exposure and food allergy? A systematic review.
        Pediatr Allergy Immunol. 2013; 24: 311-320
        • Martino D.
        • Joo J.E.
        • Sexton-Oates A.
        • et al.
        Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy.
        Epigenetics. 2014; 9: 998-1006
        • Strachan D.P.
        Hay fever, hygiene, and household size.
        BMJ. 1989; 299: 1259-1260
        • Alm J.S.
        • Swartz J.
        • Björkstén B.
        • et al.
        An anthroposophic lifestyle and intestinal microflora in infancy.
        Pediatr Allergy Immunol. 2002; 13: 402-411
        • Thorburn A.N.
        • Macia L.
        • Mackay C.R.
        Diet, metabolites, and “Western-lifestyle” inflammatory diseases.
        Immunity. 2014; 40: 833-842
        • Valenta R.
        The future of antigen-specific immunotherapy of allergy.
        Nat Rev Immunol. 2002; 2: 446-453
        • Valenta R.
        • Ball T.
        • Focke M.
        • et al.
        Immunotherapy of allergic disease.
        Adv Immunol. 2004; 82: 105-153
        • Han Y.
        • Kim J.
        • Ahn K.
        Food allergy.
        Korean J Pediatr. 2012; 55: 153-158
        • Ortolani C.
        • Ispano M.
        • Pastorello E.
        • et al.
        The oral allergy syndrome.
        Ann Allergy. 1988; 61: 47-52
        • Ebner C.
        • Birkner T.
        • Valenta R.
        • et al.
        Common epitopes of birch pollen and apples-studies by Western and Northern blot.
        J Allergy Clin Immunol. 1991; 88: 588-594
        • Valenta R.
        • Kraft D.
        Type 1 allergic reactions to plant-derived food: a consequence of primary sensitization to pollen allergens.
        J Allergy Clin Immunol. 1996; 97: 893-895
        • Bartnikas L.M.
        • Gurish M.F.
        • Burton O.T.
        • et al.
        Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis.
        J Allergy Clin Immunol. 2013; 131: 451-460
        • Noti M.
        • Kim B.S.
        • Siracusa M.C.
        • et al.
        Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.
        J Allergy Clin Immunol. 2014; 133: 1390-1399
        • Asero R.
        • Antonicelli L.
        Does sensitization to foods in adults occur always in the gut?.
        Int Arch Allergy Immunol. 2011; 154: 6-14
        • Breiteneder H.
        • Mills E.N.
        Molecular properties of food allergens.
        J Allergy Clin Immunol. 2005; 115: 14-23
        • Astwood J.D.
        • Leach J.N.
        • Fuchs R.L.
        Stability of food allergens to digestion in vitro.
        Nat Biotechnol. 1996; 14: 1269-1273
        • Groschwitz K.R.
        • Hogan S.P.
        Intestinal barrier function: molecular regulation and disease pathogenesis.
        J Allergy Clin Immunol. 2009; 124: 3-20
        • Irvine A.D.
        • McLean W.H.
        • Leung D.Y.
        Filaggrin mutations associated with skin and allergic diseases.
        N Engl J Med. 2011; 365: 1315-1327
        • Perrier C.
        • Corthésy B.
        Gut permeability and food allergies.
        Clin Exp Allergy. 2011; 41: 20-28
        • Johansen F.E.
        • Pekna M.
        • Norderhaug I.N.
        • et al.
        Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice.
        J Exp Med. 1999; 190: 915-922
        • Karlsson M.R.
        • Johansen F.E.
        • Kahu H.
        • et al.
        Hypersensitivity and oral tolerance in the absence of a secretory immune system.
        Allergy. 2010; 65: 561-570
        • Grammatikos A.P.
        The genetic and environmental basis of atopic diseases.
        Ann Med. 2008; 40: 482-495
        • Paul W.E.
        Interleukin 4/B cell stimulatory factor 1: one lymphokine, many functions.
        FASEB J. 1987; 1: 456-461
        • Romagnani S.
        The Th1/Th2 paradigm.
        Immunol Today. 1997; 18: 263-266
        • Vercelli D.
        • Geha R.S.
        Regulation of isotype switching.
        Curr Opin Immunol. 1992; 4: 794-797
        • Henderson L.L.
        • Larson J.B.
        • Gleich G.J.
        Maximal rise in IgE antibody following ragweed pollination season.
        J Allergy Clin Immunol. 1975; 55: 10-15
        • Naclerio R.M.
        • Adkinson Jr., N.F.
        • Moylan B.
        • et al.
        Nasal provocation with allergen induces a secondary serum IgE antibody response.
        J Allergy Clin Immunol. 1997; 100: 505-510
        • Niederberger V.
        • Ring J.
        • Rakoski J.
        • et al.
        Antigens drive memory IgE responses in human allergy via the nasal mucosa.
        Int Arch Allergy Immunol. 2007; 142: 133-144
        • Mojtabavi N.
        • Dekan G.
        • Stingl G.
        • et al.
        Long-lived Th2 memory in experimental allergic asthma.
        J Immunol. 2002; 169: 4788-4796
        • Kulig M.
        • Bergmann R.
        • Klettke U.
        • et al.
        Natural course of sensitization to food and inhalant allergens during the first 6 years of life.
        J Allergy Clin Immunol. 1999; 103: 1173-1179