Abstract
Immunoglobulin E (IgE)-mediated food allergy is an adverse reaction to foods and is driven by uncontrolled type-2 immune responses. Current knowledge cannot explain why only some individuals among those with food allergy are prone to develop life-threatening anaphylaxis. It is increasingly evident that the immunologic mechanisms involved in developing IgE-mediated food allergy are far more complex than allergic sensitization. Clinical observations suggest that patients who develop severe allergic reactions to food are often sensitized through the skin in early infancy. Environmental insults trigger epidermal thymic stromal lymphopoietin and interleukin-33 (IL-33) production, which endows dendritic cells with the ability to induce CD4 +TH2 cell-mediated allergic inflammation. Intestinal IL-25 propagates the allergic immune response by enhancing collaborative interactions between resident type-2 innate lymphoid cells and CD4 +TH2 cells expanded by ingested antigens in the gastrointestinal tract. IL-4 signaling provided by CD4 +TH2 cells induces emigrated mast cell progenitors to become multi-functional IL-9-producing mucosal mast cells, which then expand greatly after repeated food ingestions. Inflammatory cytokine IL-33 promotes the function and maturation of IL-9-producing mucosal mast cells, which amplify intestinal mastocytosis, resulting in increased clinical reactivity to ingested food allergens. These findings provide the plausible view that the combinatorial signals from atopic status, dietary allergen ingestions, and inflammatory cues may govern the perpetuation of allergic reactions from the skin to the gut and promote susceptibility to life-threatening anaphylaxis. Future in-depth studies of the molecular and cellular factors composing these stepwise pathways may facilitate the discovery of biomarkers and therapeutic targets for diagnosing, preventing, and treating food allergy.
Highlights
Food allergy has emerged as a major health problem worldwide because of the rapid increase in prevalence over the past decade
Considerable evidence has led to a plausible hypothesis that details the stepwise mechanisms involved in the development of food allergy: (i) in the allergic sensitization phase, exogenous molecules acting as mucosal T helper type 2 (TH2) adjuvants and filaggrin as a genetic predisposing factor may initiate inflammatory reactions to induce the production of epidermal thymic stromal lymphopoietin (TSLP) or IL-33 that triggers allergic sensitization to contacted food allergens before the establishment of oral tolerance[53,54,55,56]
TSLP endows dendritic cell (DC) and potentiates basophil function to promote a TH2-permissive microenvironment, which induces CD4+TH2 cells to differentiate and maintain antigen-specific CD4+TH2 memory/effector cells[16,18,19,57], which migrate to a draining lymphoid node and induce antigen-specific immunoglobulin E (IgE) generation. (ii) In the allergy propagation phase, re-exposure to ingested food antigens activates emigrated antigen-specific CD4+TH2 memory/effector cells in the small intestine to produce IL-13, resulting in the increase of intestinal IL-25 production
Summary
Food allergy has emerged as a major health problem worldwide because of the rapid increase in prevalence over the past decade. Allergic sensitization results in the increase of intestinal IL-25 expression, which potentiates the development of allergic reactions to ingested antigens[37] Compared with their wild-type controls, genetically modified murine strains that produce intestinal-specific IL-25 constitutively or that lack the IL-25 receptor, IL-17RB, are more susceptible or resistant, respectively, to developing IgE-mediated experimental food allergy[37]. It appears that in addition to promoting allergic reactions to ingested foods, intestinal MCs can provide an IL-4 signal to induce a TH2 cell program in regulatory T cells, resulting in the impairment of regulatory T-cell function and the loss of tolerance[52] Given their anatomical location, characteristics, and function, MMC9s may be a key player that bridges the crosstalk between the skin and gut by perpetuating allergic reactions and amplifying anaphylactic responses to dietary proteins. These findings represent a new conceptual paradigm by linking atopic status (IL-4), dietary antigen and IgE/FcεR complex interactions, and inflammatory cues (exemplified by IL-33) with MMC9 biology and food allergy (Figure 1)
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