Immune Basis of Allergic Reactions to Food

Abstract

Food allergies are diseases where the normal tolerance response to oral antigens is altered. Recent advances have begun to uncover mechanisms that mediate sensitization to food allergens and maintenance of the disease. Production of alarmins by epithelial cells triggers a cascade that leads to allergen-specific IgE synthesis. IL-9 has also been shown to play a role in mast cell recruitment and amplification of the allergic response. In recent years, increasing evidence suggests that sensitization to food allergens can be developed via nonoral routes, in particular the skin, thus leading to the "dual exposure hypothesis". Environmental factors such as diet or microbiota can shape the immune system to promote tolerance or sensitization to food antigens. While the mechanism of primary tolerance to food antigens is quite clear, that leading to permanent tolerance in food-allergic individuals through immunotherapy is still under study. Understanding the mechanisms by which oral tolerance is suppressed and sensitization develops will help to identify new targets to develop combined therapies for the treatment of food allergies.

Mechanisms of allergen-specific immunotherapy for allergic rhinitis and food allergies

“…Sensitization to food can happen through the oral route but sensitization can also occur through the skin, or occasionally through the airways. In the context of FA, the development of regulatory T (Treg) cells is compromised and instead there is polarization of the Treg cells toward the Th2 phenotype characterized by IL-4 production [59]. Peripheral blood mononuclear cells (PBMCs) from milk-allergic children after culturing with milk β-lactoglobulin for 5 days and restimulation with PMA and ionomycin have elevated IL-4 and IL-13 expression in their milk-specific Tregs comparing with PBMCs from control subjects or from peanut-allergic children without milk allergy [59,60].…”

“…In the context of FA, the development of regulatory T (Treg) cells is compromised and instead there is polarization of the Treg cells toward the Th2 phenotype characterized by IL-4 production [59]. Peripheral blood mononuclear cells (PBMCs) from milk-allergic children after culturing with milk β-lactoglobulin for 5 days and restimulation with PMA and ionomycin have elevated IL-4 and IL-13 expression in their milk-specific Tregs comparing with PBMCs from control subjects or from peanut-allergic children without milk allergy [59,60]. Besides Th2 cells, ILCs, basophils [61,62] and T follicular helper cells (Tfh) [59,63] also secrete IL-4 to further enhance the type 2 immune responses.…”

“…Peripheral blood mononuclear cells (PBMCs) from milk-allergic children after culturing with milk β-lactoglobulin for 5 days and restimulation with PMA and ionomycin have elevated IL-4 and IL-13 expression in their milk-specific Tregs comparing with PBMCs from control subjects or from peanut-allergic children without milk allergy [59,60]. Besides Th2 cells, ILCs, basophils [61,62] and T follicular helper cells (Tfh) [59,63] also secrete IL-4 to further enhance the type 2 immune responses. The IL-4 produced drives B-cell class switching to IgE and these allergen-specific IgE (sIgE) is crucial to the development of food allergies [64].…”

“…Natural oral tolerance involves active suppression of antigen-specific immune responses induced in the gastrointestinal tract and such oral tolerance requires robust induction of Treg cells within the mucosa and is initiated by CD103 + DCs, which capture antigen in the lamina propria and migrate to the mesenteric lymph nodes. In response to antigen presentation by the CD103 + DCs under a transforming growth factor β (TGF-β) and retinoic acid-dependent mechanism, naïve T cells differentiate to Tregs [59,[80][81][82]. Retinoic acid induces expression of C-C motif chemokine receptor 9 (CCR9) and α4β7 gut-homing markers by T cells [59,83] and gut-homing markers expressing antigen-specific Tregs migrate from the lymph nodes to the lamina propria, where they expand following production of IL-10 by C-X3-C motif chemokine receptor 1 (CX3CR1) + macrophages [59,84].…”

“…In response to antigen presentation by the CD103 + DCs under a transforming growth factor β (TGF-β) and retinoic acid-dependent mechanism, naïve T cells differentiate to Tregs [59,[80][81][82]. Retinoic acid induces expression of C-C motif chemokine receptor 9 (CCR9) and α4β7 gut-homing markers by T cells [59,83] and gut-homing markers expressing antigen-specific Tregs migrate from the lymph nodes to the lamina propria, where they expand following production of IL-10 by C-X3-C motif chemokine receptor 1 (CX3CR1) + macrophages [59,84]. Goblet cell-associated antigen passages (GAPs) in the intestinal epithelium forms to deliver antigen exclusively to the tolerogenic CD103 + CXC3CR1 − DCs, favoring the induction of Tregs.…”