Food allergy: an enigmatic epidemic

Abstract

Food allergy is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Current research efforts are focused on understanding the immune basis of food allergy, identifying environmental factors that may contribute to its rising prevalence, and developing immunotherapeutic approaches to establish immune tolerance to foods. Technological advances such as peptide microarray and MHC class II tetramers have begun to provide a comprehensive profile of the immune response to foods. The burgeoning field of mucosal immunology has provided intriguing clues to the role of the diet and the microbiota as risk factors in the development of food allergy. The purpose of this review is to highlight significant gaps in our knowledge that need answers to stem the progression of this disorder that is reaching epidemic proportions.

Keywords: IgE; Th2; Treg; anaphylaxis; immunotherapy; microbiota; mucosal immunology.

Figure 1. Factors contributing to clinical reactivity to foods

The presence of food-specific IgE is not sufficient to predict clinical reactivity to foods, therefore other co-factors are needed. In a sensitized individual, allergen ingestion by the oral route can lead to clinical manifestations secondary to activation of systemic allergic effector cells by cross-linking IgE bound to effector cells through the FcεRI receptor. Highlighted in red are open questions about mechanisms contributing to the clinical reactivity to foods. Factors altering the absorption of food allergens from the intestine (e.g. food matrix, food processing such as heating), or preventing the proteolytic digestion of food allergens (e.g. antacid, food matrix, food processing) may determine whether clinical reactivity to foods occurs. The nature of the IgE response (affinity, clonality, linear versus conformational epitopes, and to which antigens within a food) will determine if activation of effector cells will occur. Questions remain about the relative contribution of mast cells and basophils in human food allergy, and the possible contribution of other effector cells or antibodies that have been shown to play a role in the mouse. In the grey box are mechanisms that are thought to suppress clinical reactivity to foods, and may play a role in the development of clinical tolerance. These include IgA and IgG4 that function as blocking antibodies and prevent IgE-mediated effector cell degranulation or IgE-facilitated antigen presentation, and Tregs that may suppress food allergy by blocking the generation of IgE (through blocking Th2 cells) or directly suppressing allergic effector cells.

Figure 2. Potential factors contributing to sensitization to foods

Environmental factors may provide an increased or decreased risk for the development of allergic sensitization to foods. The gut microbiota has been shown to suppress allergy by decreasing IgE, decreasing allergic effector cells (basophils), and increasing Tregs in the intestine. Nutritional factors may either suppress or promote allergy. Data show that vitamin A and D may promote tolerance or suppress allergy, as do long chain fatty acids (FA) and aryl hydrocarbon receptor (AHR) ligands. In contrast, high fat diet and medium chain trigylcerides (TG) promote allergy. Exposure to food allergens through non-oral routes such as the skin may predispose to sensitization, particularly in the context of genetic barrier defects or inflamed skin. Inflamed skin produces cytokines that change the phenotype of the dendritic cell and promote Th2 polarization. Allergens themselves can activate innate immune responses in dendritic cells to promote Th2 polarization.