Food allergy: immune mechanisms, diagnosis and immunotherapy

Abstract

Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

Figure 1. Immune tolerance to oral antigens in the gut

CX₃CR1⁺ cells (most likely to be macrophages) extend dendrites between the intestinal epithelial cells, sample antigens in the gut lumen^, and transfer captured antigens via gap junctions to CD103⁺ dendritic cells (DCs). A subset of these DCs migrates from the lamina propria to the draining lymph nodes where the DCs express transforming growth factor-β (TGFβ) and retinoic acid, thereby inducing naive T cells to differentiate into regulatory T (T_reg) cells^,. Macrophages also seem to secrete interleukin-10 (IL-10), leading to T_reg cell proliferation^,,; however, this is debated. Several types of regulatory T cell (resting, effector, and memory) have been reported to be associated with mucosal tolerance, including induced forkhead box P3 (FOXP3)⁺ T_reg cells, IL-10-secreting Tr1 cells and TGFβ-secreting T helper 3 (T_H3) cells. Retinoic acid also induces T_reg cell expression of integrin α4β7, which results in homing to the gut where T_reg cells may dampen the immune response^,,. CD103⁺ DCs also sample antigens that pass through the epithelial barrier via M cell-mediated transcytosis or through translocation by mucin-secreting goblet cells; under some circumstances, CD103⁺ DCs may capture antigens from the lumen directly, via periscoping behaviour (extending a process through a tight junction) or by extending a process through a transcellular pore in an M cell. B cell clones expressing antibody specific for food allergen may undergo isotype switching in the secondary lymphoid organs with the aid of follicular T helper (T_FH) cells. Food tolerance and allergen desensitization are associated with IgA (FIG. 1) and IgG4 (FIG. 3), respectively^,. By contrast, food allergen-specific IgE (FIG. 2) will be bound by FcεRI on mast cells (which are normally found in tissues forming environmental barriers) and basophils, thus leading to immediate hypersensitivity reactions to food. High-dose exposure to oral antigens has been reported to lead to the anergy or deletion of antigen-specific T cells, possibly after DC interaction. T_FH cells secreting different cytokine combinations favour B cell switch recombination to produce particular antibody isotypes, whereas follicular T_reg cells suppress the germinal centre reaction^,. The roles of tissue-resident T cells, CD8⁺ T cells and γδ T cells remain to be determined. The relationship between T_FH cells and the conventional T_H cell subsets is not clear, and conversion between the two has been reported^,. CTLA4, cytotoxic T lymphocyte antigen 4.

Figure 2. T_H2 cell-mediated inflammatory response to oral antigen in the gut

Epithelial damage or inflammation (for example, due to toxin exposure or trauma) in the gut, skin (not shown) or airways (not shown) allows increased antigen entry and promotes the secretion of the epithelium-derived cytokines interleukin-25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). These mediators ‘set’ the immune system towards a T helper 2 (T_H2) cell response, and it is thought that the initial sensitization to food allergens often takes place at the skin^,. In particular, TSLP may promote dendritic cell (DC) differentiation into a T_H2 cell-promoting phenotype^,. For example, OX40L may be upregulated in DCs that promote T_H2 cell differentiation of naive CD4⁺ T cells. IL-25 secretion by epithelial tuft cells also may aid the expansion of type 2 innate lymphoid cell (ILC2) populations, which together with T_H2 cells secrete cytokines that promote the T_H2 cell-mediated immune response, which includes tissue eosinophil accumulation and IgE class-switching by B cells. T_H9 cells also contribute to the allergic immune response by increasing tissue mast cell accumulation, and IL-4-mediated signalling may convert regulatory T cells into T_H2 cells. The roles of follicular T cells, tissue-resident T cells, CD8⁺ T cells and γδ T cells remain to be determined. T_reg cell, regulatory T cell.

Figure 3. Desensitization to oral antigens in the gut

Differences between the immune responses associated with desensitization and tolerance are under active investigation. Initially during desensitization, mast cell and basophil activation are decreased through an unclear mechanism, and a shift occurs from the predominance of T helper 2 (T_H2) cells to that of allergen-specific T_reg cells, which in turn may lead to the observed shift in allergen-specific antibodies from the IgE to the IgG4 isotype^,. As has been proposed in immunotherapy for venom allergies, IgG4 antibodies may compete with IgE antibodies for food allergens, further dampening the T_H2 cell-mediated immune response^,. The source of these IgG4 antibodies may be regulatory B cells, which also promote immune tolerance through the secretion of IL-10 (REF. 90). The proposed mechanism of dendritic cell (DC) inhibition by regulatory T (T_reg) cells is possibly mediated via cytotoxic T lymphocyte antigen 4 (CTLA4) and lymphocyte activation gene 3 (LAG3). T_reg cells inhibit mast cells via contact involving OX40–OX40L interaction. The roles of follicular T cells, tissue-resident T cells, CD8⁺ T cells and γδ T cells remain to be determined.