IL-9-producing cells in the development of IgE-mediated food allergy

Abstract

Food allergy is a harmful immune reaction driven by uncontrolled type 2 immune responses. Considerable evidence demonstrates the key roles of mast cells, IgE, and TH2 cytokines in mediating food allergy. However, this evidence provides limited insight into why only some, rather than all, food allergic individuals are prone to develop life-threatening anaphylaxis. Clinical observations suggest that patients sensitized to food through the skin early in life may later develop severe food allergies. Aberrant epidermal thymic stromal lymphopoietin and interleukin (IL) 33 production and genetic predisposition can initiate an allergic immune response mediated by dendritic cells and CD4⁺TH2 cells in inflamed skin. After allergic sensitization, intestinal IL-25 and food ingestion enhance concerted interactions between type 2 innate lymphoid cells (ILC2s) and CD4⁺TH2 cells, which perpetuate allergic reactions from the skin to the gut. IL-4 and cross-linking of antigen/IgE/FcεR complexes induce emigrated mast cell progenitors to develop into the multi-functional IL-9-producing mucosal mast cells, which produce prodigious amounts of IL-9 and mast cell mediators to drive intestinal mastocytosis in an autocrine loop. ILC2s and TH9 cells may also serve as alternative cellular sources of IL-9 to augment the amplification of intestinal mastocytosis, which is the key cellular checkpoint in developing systemic anaphylaxis. These findings provide a plausible view of how food allergy develops and progresses in a stepwise manner and that atopic signals, dietary allergen ingestion, and inflammatory cues are fundamental in promoting life-threatening anaphylaxis. This information will aid in improving diagnosis and developing more effective therapies for food allergy-triggered anaphylaxis.

Figure 1. Potential involvements of intestinal IL-9-producing cells in the development of immunoglobulin E (IgE)-mediated food allergy

In the allergic sensitization phase, environmental or mechanical triggers (or both) may induce skin keratinocytes to produce thymic stromal lymphopoietin (TSLP), which recruits and activates dendritic cells (DCs). TSLP-activated DCs migrate to draining lymph nodes to induce naïve CD4⁺T cells to differentiate into CD4⁺TH2 cells and maintain CD4⁺TH2 effector/memory pools. TSLP may also promote the generation of TH9 cells after sensitization occurs. In the allergy propagation phase, these CD4⁺TH2 cells migrate to the intestine and interact with resident type-2 innate lymphoid cells (ILC2s) to produce large amounts of IL-13 in response to intestinal IL-25 stimulation. In the amplification-of-mastocytosis phase, IL-4 signals provided by CD4⁺TH2 cells induce emigrated mast cell progenitors (MCPs) to become the multi-functional IL-9-producing mucosal mast cells (MMC9s), which then expand greatly after ingested antigens cross-link with MMC9 surface IgE/FcεR complex. The inflammatory cytokine IL-33 enhances IL-9 production by MMC9s, resulting in MMC9 maturation and the amplification of intestinal mastocytosis in an autocrine loop. In addition, IL-25 may direct act on TH9 cells to promote IL-9 production, resulting in the enhanced intestinal anaphylaxis. Thus, MMC9 induction may serve as a key cellular checkpoint to amplify and propagate allergic inflammation, resulting in the development of IgE-mediated food allergy. MMC, mucosal mast cell; STAT6, signal transducer and activator of transcription 6; TH2, T helper type 2 cell.