Food Allergy

Adverse reactions to foods are classified as either food hypersensitivity (allergy) or food intolerance. IgE-mediated hypersensitivity accounts for the majority of well-characterized food allergic reactions, although non-IgE-mediated immune mechanisms are believed to be responsible for a variety of hypersensitivity disorders. This chapter examines adverse food reactions that are IgE mediated and non-IgE mediated and those entities that have characteristics of both. The true prevalence of adverse food reactions is still unknown. The vast majority of food allergic reactions are secondary to a limited number of foods. Oral tolerance to food allergens occurs as the result of an appropriate suppression of the immune system when the gut mucosa comes in contact with dietary proteins. Gastrointestinal clinical manifestations are generally milder, and histologic examination of the gut mucosa shows less-extensive changes than with those patients presenting with primary gastrointestinal disease. Celiac disease is an extensive enteropathy leading to malabsorption. Once the diagnosis of food allergy is established, the only proven therapy is the strict elimination of the food from the patient’s diet. Certain factors place some individuals at increased risk for more severe anaphylactic reactions: (i) history of a previous anaphylactic reaction; (ii) history of asthma, especially if poorly controlled; (iii) allergy to peanuts, nuts, fish, and shellfish; (iv) use of ß-blockers or angiotensin-converting enzyme inhibitors; and (v) (possibly) being female. Primary prevention of food allergies relates to blocking immunologic sensitization to foods. Patient education and support are essential for food-allergic patients.

The recently revised nomenclature for allergic diseases includes several manifestations of food allergy such as asthma, urticaria and/or angioedema, anaphylaxis, eczema, and rhinitis. The aim of a correct diagnosis of food allergy is to establish a causal relationship between food ingestion and the clinical symptoms reported by the patient and to identify the triggering allergen and the immune mechanism determining the reaction. The current approach to food allergy diagnosis using well-established tools including medical history, skin test (ST), immunoglobulin E (IgE) detection, and oral challenge, sich as double-blind placebocontrolled food challenge (DBPCFC) is depicted. The use of flow cytometry has increased the use of basophil activation testing to confirm the diagnosis of food allergy. Allergenic molecules can be used as the most objective tool for the best diagnosis and unequivocal identification of affected subjects molecules can be used as the most objective tool for the best diagnosis and unequivocal identification of affected subjects. A combination of in vivo and in vitro tools are needed to reach a good level of diagnostic reliability in food allergy diseases. Great expectations arise from the combined use of allergens obtained by molecular biology techniques, exactly as they are seen and processed by the immune system, sophisticated assays that allow suitable multiple-IgE detection of hundreds of allergenic molecules and global sharing of a huge mass of data. This novel approach will represent developments that are not too far in the future for food allergy diseases.

Peanuts, tree nuts, cow’s milk, soy, wheat, hen’s egg, fish, and crustaceans are considered the “Big Eight” foods in discussions of immunoglobulin E (IgE)-mediated or -associated food allergy both internationally and in the United States. These foods account for approximately 90% of food allergies in the best-studied group in the United States: children with atopic dermatitis. Although the Big Eight foods account for about 90% of clinical reactions in children with atopic dermatitis in referral centers, the pattern of foods causing reactions prompting emergency department visits is somewhat different in the United States. However, the Big Eight foods remain highly useful for labeling rules because the vast majority of individuals with food allergy will be helped, and specific fruits or vegetables are easier to avoid once the allergy is identified and the patient receives appropriate education on avoidance. The chapter reviews the eight dominant foods associated with food allergic reactions along with sesame. Cow's milk allergy is the most common food allergy in infants reported from developed Western nations. Most infants with IgE-mediated or IgE-associated allergy to cow’s milk protein will do well on isolated soy protein-based formula and that there is no need to spend money on more expensive, less-palatable formulas.

Excessive immune responses to commensals or to food antigens will result in autoimmunity or food allergy. Despite the progress in knowledge regarding the interactions between food antigens and the gut, unanswered questions remain. The chapter addresses these questions by bringing together recent findings on the ways in which different components of the gut tract respond to foods, commensals, and pathogens in a systematic overview. It is structured as follows. First, a descriptive section presents a brief outline of the spatially distinct immune decision-making units and their integrative interactions, including discussion of the cellular and molecular structures involved in gastrointestinal responses to foods, commensal bacteria, and pathogens, as grouped in the proposed autonomous structures. This is followed by an overview of the role of development in determining the outcome of gut responses to foods, since such responses are also influenced by the history of previous exposures to food antigens in utero and after birth. The evolution of the mother-child integrated immunological unit from fetal life to the end of the breast-feeding period is discussed, as well as characterization of the pathological immune responses to foods that occur in the gut and intestinal autoimmune diseases and food allergies. Finally, the chapter describes the preventive and therapeutic proposed uses of oral tolerance and the perspectives and the questions that still remain unanswered.

This chapter addresses the relationship of the CD4+ helper T-cell epitope immunodominance to pathways of allergen-antigen processing, as they are directed by protein three-dimensional structures. Allergy is recognized as a failure of immune tolerance by CD4+ T cells. The organization of sections in this chapter is inspired by the steps in the development of immune tolerance and allergy. Several sections deal with general features of the process: a discussion of the cells that process and present food allergens; a discussion of the lysosomal enzymes that process allergens; a brief summary of evidence that proteolytic processing follows pathways that could depend on molecular and cellular contexts; evidence that antigen processing and peptide loading occur in the same compartment, where the two mechanisms may interact; the idea that tolerance and immunity represent different outcomes of the same mechanism of antigen processing; and a summary of the most direct evidence that the antigen-allergen structure has an influence on epitope dominance, including a discussion of the nature of structural data and how it is used. A section discusses the relationship of structure and epitope dominance for human immunodeficiency virus (HIV) gp120 and several food allergens: chicken lysozyme, chicken ovalbumin, bovine ß-lactoglobulin (BLG), and the birch tree aeroallergen Bet v 1. The final section discusses the implications of the relationship of structure to dominance on the development of allergy, evolution of the immune system, and allergy immunotherapy.

Food allergy is a major cause of life-threatening hypersensitivity reactions. Currently, the avoidance of the allergenic food is the only method of preventing further reactions for allergic patients. Even with good educational information, 50% of allergic patients have accidental ingestions and allergic reactions over a 24-month period. With better characterization of allergens and an understanding of the immunologic mechanism involved in this reaction, investigators have developed several therapeutic modalities potentially applicable to the treatment and eventual prevention of food allergy. Techniques under current investigation for the treatment of food allergy include peptide immunotherapy, traditional Chinese medicine, mutated protein immunotherapy, allergen DNA immunization, vaccination with immunostimulatory DNA sequences, and anti-IgE therapy. While peptide immunotherapy for food allergy has not yet reached clinical trials, studies utilizing the peptides of the peanut allergens are interesting and suggest a possible role for peptide immunotherapy in the future therapy of food allergy. New therapies currently under investigation should help the physician greatly improve care for food-induced allergic reactions while reducing the risk of anaphylaxis in these patients.

Animal models have been used to provide insight into the complex immunological and pathophysiological mechanisms of human type I allergic diseases. Therapeutic studies include allergen modifications, route of exposure, tolerance development with bacterial agents and/or herbal medicines, and cytokine skewing. Allergenic potential of novel proteins has received substantial interest in recent years, aimed at predicting allergenicity for genetically modified foods based upon known allergens, rare allergens, and nonallergens in different animal models. This chapter takes information from these sources and others to provide the reader with the author’s perspective on animal models and food allergy that could extrapolate to human type I allergic disease. An ideal food allergy animal model should include the following features. This chapter highlights the IgE-mediated gastrointestinal food hypersensitivity disorders (gastrointestinal anaphylaxis; oral allergy syndrome). The normal immune response in animals to dietary proteins is oral tolerance; however, abrogation of active immune suppression can result in adverse reactions, such as IgE-mediated food allergy. The chapter concludes that the most difficult task from one or more of these promising animal studies should be to extrapolate successfully to human disease.

Food allergies have become an increasingly important food safety issue in recent years. The current approaches for the prevention of future reactions are focused on the evaluation of the inadvertent presence of allergenic material in food and the identification of the allergen on labels by the consumer governed by the implementation of new regulations in several countries. Depending on the type of target molecule, protein, or DNA, the current detection methods for food allergens can be classified as immunoassay or polymerase chain reaction (PCR). Immunoassay is a very versatile technique because it uses antibodies that have the ability to detect a very specific protein(s) (allergen[s]) within a complex mixture of compounds. On the other hand, PCR targets the gene encoding the protein or allergen of interest. This chapter provides an overview of the current trends for the detection of food allergens, based on published information and the factors and steps involved in the analysis process. Moreover, special attention will be focused on commercially available kits. A section discusses the future approaches, such as the applicability of proteomics and genomics in the field, automation of analysis procedures, and confirmatory methods. From the point of view of detection of food allergens by immunoassay, allergenic proteins are comparable to nonallergenic proteins in that they are both antigens that are detected by IgG antibodies. As technology advances, new analytical techniques are being applied to the field of detection of food allergens or the characterization of new ones.

The allergenicity assessment of genetically modified organisms (GMOs) crops or GM organisms (GMOs) is one of the important steps in evaluating whether food and feed products from new varieties of plants and animals developed using biotechnology should be safe to eat or would pose a real health risk to the consumer. However, if the introduced gene encoded a major allergen that was transferred into a different food crop, the risk would be substantial for individuals with existing allergies to that protein. This chapter is devoted primarily to evaluating whether the introduced protein is an allergen or is sufficiently similar to suspect potential cross-reactivity, with strong emphasis on the use of computer sequence comparisons between the introduced protein and known allergens. A critical step in the assessment is the use of computer sequence comparisons or bioinformatics to evaluate the similarity of the introduced protein to those of known allergens. Food and Drug Administration (1992) recommended that the allergenicity assessment of GM crops focus on testing to ensure that the allergenicity of the GM variety is not greater than that of the traditionally produced varieties of the same crop. As described, the assessment of each new GM crop should evaluate the known allergenicity of the source of the gene, to help design an appropriate testing strategy. The allergenicity assessment and our understanding of allergenic cross-reactivity in general may be improved by additional studies of clinically responsive subjects with clear histories of allergic reactions to multiple related foods.

The ability of a food or a food protein to cause allergic sensitization and to elicit an allergic reaction is the result of a complex set of interactions involving both the immune and digestive systems. It may be possible to infer potential allergenicity by comparing a protein of interest to known allergenic proteins. One major tool for conducting such a comparison is bioinformatic analysis. Bioinformatics can be used to compare primary sequences, secondary and tertiary structures, functional classifications, and evolutionary relationships for entire proteins or for domains within proteins. The utility of these comparisons depends on the availability of both appropriate data sources and analytical tools. Just as chemical or biological analyses should use characterized reagents and validated methods, bioinformatic analyses should be conducted using characterized databases and validated algorithms. Although a number of allergy-related databases are available, they are very different in design and content and in the degree to which information characterizing the content of the database is made available to users. A similar diversity exists among the available analytical resources for assessing potential allergenicity, and no standards or procedures have been developed for validating these resources. To illustrate the extent of the diversity among allergen-related bioinformatic resources, representative online allergen databases and analytical resources are described below. Based on the descriptive information available for each of these resources, principles of good database practice (GDP) can be developed that will maximize the utility of these resources.

The Structural Database of Allergenic Proteins (SDAP) brings together data from diverse sources on over 800 allergen sequences and their epitopes in a cross-referenced format. Special methods developed for SDAP, such as the property distance (PD) scale, automatically detect peptides in the ensemble of allergen sequences that have physicochemical properties similar to known immunoglobulin E (IgE) epitopes. Comparing the structure of food allergens with allergenic proteins from exposure to pollens, insect dust, or other aeroallergens can give valuable information about the sensitization process. Any novel protein introduced into a food crop should have a low potential to be an allergen. This chapter deals with database approaches to determine the allergenic potential of a test protein, based on similarity to known allergens. It outlines basic methodology to identify cross-reacting proteins in food sources and predict the potential allergenicity of novel proteins. The chapter concentrates on the SDAP, which has been specifically designed to allow combined analysis of the sequence, structure, and epitopes of allergens. It also shows how SDAP and the methods for sequence and peptide comparison incorporated therein can be used to predict cross-reactive allergens in foods and determine common properties of their IgE epitopes. The second half of the chapter demonstrates how SDAP has allowed one to rapidly collect data pertinent to very basic questions about allergens, such as whether enzymatic activity is related to allergenicity. The chapter provides an overview of the information and methods incorporated into the cross-referenced (MySQL-Linux) lists of data.