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Common food allergens

Food Allergy

Food Allergies and Allergens

Douglas H. Jones, MD, FAAAAI, FACAAI 
Reviewed on June 20, 2024
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Introduction

Food allergies represent a significant public health concern, affecting millions of people worldwide, with highest prevalence in developed countries. Food allergies occur when the immune system reacts abnormally to certain foods, which can cause a range of symptoms – from mild discomfort to severe, life-threatening reactions. The Food and Drug Administration(FDA) has traditionally recognized eight major food allergens – milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybeans – as responsible for the majority of allergic reactions in the United States. However, in April 2021, the Food Allergy Safety, Treatment, Education and Research (FASTER) Act designated sesame as the ninth major food allergen, with the change taking effect on January 1, 2023. While some allergies typically resolve during childhood (e.g., those to milk, egg, wheat and soy) others tend to persist into adulthood. Understanding the genetic basis and the immune…

Introduction

Food allergies represent a significant public health concern, affecting millions of people worldwide, with highest prevalence in developed countries. Food allergies occur when the immune system reacts abnormally to certain foods, which can cause a range of symptoms – from mild discomfort to severe, life-threatening reactions. The Food and Drug Administration (FDA) has traditionally recognized eight major food allergens – milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybeans – as responsible for the majority of allergic reactions in the United States. However, in April 2021, the Food Allergy Safety, Treatment, Education and Research (FASTER) Act designated sesame as the ninth major food allergen, with the change taking effect on January 1, 2023. While some allergies typically resolve during childhood (e.g., those to milk, egg, wheat and soy) others tend to persist into adulthood. Understanding the genetic basis and the immune mechanisms responsible for food allergies is crucial to both an accurate diagnosis and effective management, including the development of targeted therapies.

Definition and Classification

Food allergies encompass a spectrum of adverse immune responses triggered by the ingestion of specific food proteins. The defining characteristic of a food allergy is the involvement of the immune system, which recognizes harmless food proteins as a threat, leading to an abnormal immune response. These immune responses can broadly be categorized into two main groups: immunoglobulin (Ig) E-mediated and non-IgE-mediated allergies.

IgE-Mediated Food Allergies

IgE-mediated allergies occur when tolerance – a mechanism that ensures food antigens cross the epithelial barrier without triggering an immune response – fails to develop. The loss of tolerance is called sensitization (Figure 1-1). In normal physiological circumstances (i.e., in the absence of pro-inflammatory or danger signals) antigen presenting cells (e.g., dendritic cells) release interleukin (IL) 10 and transforming growth factor beta (TGF-β), which leads to a cascade of allergic reaction-suppressing actions. Naïve T-cells differentiate into T regulatory cells, and B cells are promoted to produce IgA and IgG, which together inhibit the degranulation of effector cells. When the epithelial barrier is disrupted, more food antigens are able to enter, leading to release of the pro-inflammatory cytokines IL-25, IL-33 and thymic stromal lymphopoeitin, which activates dendritic cells and triggers the process of sensitization. The activated dendritic cells identify food antigens as a threat, inducing the differentiation of naïve T-cells into T helper 2 (Th2) cells. Th2 cells secrete IL-4, which promotes IgE production in B cells, and IL-5 and IL-13, which promote the differentiation of effector cells, including eosinophils and basophils. Additionally, some naïve T-cells differentiate into Th9 cells, which secrete IL-9, leading to the accumulation of mast cells. This T cell-mediated immune response is further promoted by type 2 innate lymphoid cells (ILC2), which secrete large quantities of all the T cell-secreted interleukins (IL-4, IL-5, IL-13, and IL-9). As a final step in sensitization, food-specific IgE binds to the receptors on mast cells and basophils. Upon re-exposure to the food allergen, the allergen binds to IgE antibodies on the surface of the effector cells, resulting in the release of histamine, tryptase, platelet-activating factor, prostaglandins, and leukotrienes into circulation (Figure 1-1). The rapid onset of action of these mediators earned IgE-mediated allergies the designation of “immediate hypersensitivity reactions”.

Enlarge  Figure 1-1: Sensitization and IgE-Mediated Immune Reaction. A) Food allergens induce dendritic cell and Th2 activation. The signaling cascade facilitated by interleukins further activates B cells, which differentiate into plasma cells responsible for IgE production. IgE antibodies then bind to the receptors on mast cells, finalizing sensitization. B) When allergens are reintroduced, they bind to IgEs, leading to mast cell degranulation as an immediate reaction and also promote the Th2 immune response as a late reaction. Source: Adapted from: Mayorga C, et al. Foods. 2021;10(5):1037.
Figure 1-1: Sensitization and IgE-Mediated Immune Reaction. A) Food allergens induce dendritic cell and Th2 activation. The signaling cascade facilitated by interleukins further activates B cells, which differentiate into plasma cells responsible for IgE production. IgE antibodies then bind to the receptors on mast cells, finalizing sensitization. B) When allergens are reintroduced, they bind to IgEs, leading to mast cell degranulation as an immediate reaction and also promote the Th2 immune response as a late reaction. Source: Adapted from: Mayorga C, et al. Foods. 2021;10(5):1037.

Non-IgE-Mediated Food Allergies

Non-IgE-mediated allergies, also known as delayed-type hypersensitivity reactions, are characterized by subacute or chronic symptoms primarily affecting the gastrointestinal (GI) tract. Non-IgE-mediated allergies include protein-induced enterocolitis syndrome (FPIES; characterized by vomiting, diarrhea and other GI symptoms), food protein induced allergic proctocolitis (FPIAP; characterized by blood-streaked or mucus-containing stools), and food-protein enteropathy (FPE; characterized by non-bloody diarrhea). The pathophysiology of non-IgE-mediated allergies is poorly understood. Food protein-induced enterocolitis syndrome is thought to result from intestinal dysregulation of innate and cellular (i.e., T cell) immune pathways. Allergic reactions associated with FPIES include activation of T cells and increased production of TNF-α and other cytokines, as well as decreased production of TGF-β, leading to inflammation in the colon and ileum. This is thought to play a role in weakening the epithelial barrier in the intestines, promoting fluid shifts into the gastrointestinal lumen. Although more focus has been put on T-cell pathways, recent studies indicate that the innate immune system may play a significant role in driving the FPIAS reaction. The activation of monocytes, neutrophils, eosinophils, lymphocytes and natural killer cells has been noted in patients with FPIES after exposure to trigger foods. Several studies demonstrated increased levels of various interleukins, including IL-2, IL-5, IL-8, IL-10 and IL-4. A study from 2021 identified a link between acute FPIES reactions and activated IL-17 pathway signaling. Humoral immunity appears to have little effect on FPIES pathogenesis, although the presence of food-specific IgE has been associated with persistent FPIES. Neuroimmune mechanisms are also implicated in the pathogenesis of FPIES, since vomiting, abdominal pain and lethargy seem to improve with the use of ondansetron (a central selective serotonin receptor antagonist) during acute episodes of FPIES. The current framework for understanding FPIES is shown in Figure 1-2.

Enlarge  Figure 1-2: FPIES Pathophysiology. ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotrophin-releasing hormone; NK, natural killer. Source: Adapted from: Baker MG, Sampson HA. Recent trends in food protein–induced enterocolitis syndrome (FPIES). J Allergy Clin Immunol. 2023;151(1):43-46.
Figure 1-2: FPIES Pathophysiology. ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotrophin-releasing hormone; NK, natural killer. Source: Adapted from: Baker MG, Sampson HA. Recent trends in food protein–induced enterocolitis syndrome (FPIES). J Allergy Clin Immunol. 2023;151(1):43-46.

The pathophysiology of FPIAP is similar to that of FPIES, while that of FPE is poorly understood, since this condition is rarely diagnosed. The pathology of FPIAP is mostly limited to the rectosigmoid colon, while FPE mainly affects the small intestine.

Mixed IgE/Non-IgE-Mediated Food Allergies

Some allergic reactions are categorized as “mixed”, i.e., both IgE and non-IgE-mediated; eosinophilic gastrointestinal disorders (EGIDs) are an example. Although an IgE-mediated reaction is not necessarily observed with EGIDs, they often involve allergic sensitization, which led to such a categorization. The category of EGIDs includes eosinophilic esophagitis (EoE), eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis and eosinophilic colitis. Like with non-IgE-mediated allergies, the pathogenesis of EGIDs is not fully understood. The two key components in EoE development are the disruption of esophageal epithelial barrier and localized Th2 inflammation in the esophagus mediated by IL-5 and IL-13.

Food Intolerance and Celiac Disease

Many patients attribute their food sensitivity to an allergy before any other condition, such as food intolerance or celiac disease (CD), making little distinction between them. However, it is important to note that these are distinct conditions with different etiologies and management strategies. The diagnosis of food allergies can pose a challenge since several factors – allergen type, reaction severity and underlying etiology – can all vary. Differentiating between several possible conditions when presented with a range of symptoms is key for making the right diagnosis and choosing the right management approach. The main characteristic of food allergies is that they are immune system-mediated reactions. Food intolerance, on the other hand, is a non-immune reaction that includes metabolic, toxic, pharmacologic and other, undefined mechanisms. The involvement (or absence of involvement) of the immune system, can serve as a diagnostic hint; however, people who continue to consume foods they are intolerant to may develop secondary gut inflammation. Furthermore, like a genuine food allergy, CD is also an immune-mediated condition, making the differential diagnosis more challenging. The most important distinction between food allergies and CD is that CD is an autoimmune condition triggered by the ingestion of gluten, rather than an anaphylactic reaction. Although both food intolerance and CD can have serious consequences if left untreated, only food allergies pose a risk of anaphylaxis which can directly endanger the patient’s life. The classification of these hypersensitivity reactions is shown in Figure 1-3.

Enlarge  Figure 1-3: The Classification of Food Hypersensitivity Reactions. Source: Based on and modified from: Skypala I. <em>J Am Diet Assoc</em>. 2011;111(12):1877-1891.
Figure 1-3: The Classification of Food Hypersensitivity Reactions. Source: Based on and modified from: Skypala I. J Am Diet Assoc. 2011;111(12):1877-1891.

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