Regulatory Immune Mechanisms in Tolerance to Food Allergy

Abstract

Oral tolerance can develop after frequent exposure to food allergens. Upon ingestion, food is digested into small protein fragments in the gastrointestinal tract. Small food particles are later absorbed into the human body. Interestingly, some of these ingested food proteins can cause allergic immune responses, which can lead to food allergy. So far it has not been completely elucidated how these proteins become immunogenic and cause food allergies. In contrast, oral tolerance helps to prevent the pathologic reactions against different types of food antigens from animal or plant origin. Tolerance to food is mainly acquired by dendritic cells, epithelial cells in the gut, and the gut microbiome. A subset of CD103⁺ DCs is capable of inducing T regulatory cells (Treg cells) that express anti-inflammatory cytokines. Anergic T cells also contribute to oral tolerance, by reducing the number of effector cells. Similar to Treg cells, B regulatory cells (Breg cells) suppress effector T cells and contribute to the immune tolerance to food allergens. Furthermore, the human microbiome is an essential mediator in the induction of oral tolerance or food allergy. In this review, we outline the current understanding of regulatory immune mechanisms in oral tolerance. The biological changes reflecting early consequences of immune stimulation with food allergens should provide useful information for the development of novel therapeutic treatments.

Keywords: dendritic cells; food allergy; food microbiome; oral tolerance; regulatory T and B cells.

Figure 1

The classification of diseases that cause by food allergy. Classification of food-related diseases by three different immune responses; IgE-mediated immediate disorders, non-IgE-mediated disorders, and disorders with the contributions from mixed IgE-mediated and cell-mediated immune pathways.

Figure 2

Mechanisms of immune tolerance to food allergens. Induction of food tolerance takes place in the gut when the immune cells encounter food antigens. Several cell types are involved in the antigen uptake: goblet cells, microfold (M) cells, intestinal epithelial cells, CX3CR1⁺ macrophages (MØ), and CX3CR1+dendritic cells. CX3CR1⁺ DCs and CX3CR1⁺ MØ, are capable of extending dendrites to capture antigens on the apical layer of epithelium in the gut lumen. Antigens taken up by CX3CR1⁺ MØ and goblet cells are transferred to CD103⁺CX3CR1⁻ DCs, which subsequently migrate to draining lymph node in a CCR7 dependent manner. Production of retinoic acid and TGF-β foster differentiation of naïve T cells into regulatory T cells (Tregs). Retinoid acid-dependent induction of integrin α4β7 expression on Tregs is responsible for T cell homing to lamina propria. Tregs (Foxp3⁺), and Th3 cells inhibit Th2-dependent allergic inflammation and mast cell degranulation, through the production of IL-10 and TGF-β. Suppression of Th2-responses also engages regulatory B cells (Bregs) that contribute to food tolerance by producing IgG4.