Novel IL-9-Producing Mucosal Mast Cells Promote IgE-Mediated Food Allergy

Rationale: IgE-mediated food allergy is manifested by an overactive T-helper 2 immune response to dietary antigens in the gastrointestinal tract. Frequency of newly identified IL-9-producing mast cells (MMC9s) correlates positively with levels of intestinal mastocytosis. We hypothesize that induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.

Methods: Involvements of MMC9s in regulating susceptibility to food allergy were examined in mouse models of food allergy. Expression levels of MMC9-associated transcripts were analyzed in duodenal biopsies of atopic patients developed food allergy.

Results: MMC9s secrete prodigious amounts of IL-9 and mast cell protease-1 in response to IL-33 and antigen/IgE complex crosslinking, respectively. By producing significant amounts of IL-9, MMC9s cause pronounced intestinal mastocytosis and the production of mast cells. Repeated intragastric antigen challenge induces significant accumulations of both MMC9s and CD4⁺TH2 cells, which correlate positively with symptoms and susceptibility of murine strains to develop experimental food allergy. The development of MMC9s requires the presence of CD4⁺TH2 cells and the proteins of IL-4 and STAT6. Mice ablated or deficient of MMC9 induction fail to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that can be restored by adoptively transferred MMC9s. Finally, atopic patients that develop food allergy display increased intestinal expression of Il9 and MC-specific transcripts.

Conclusions: MMC9s, the primary cellular source of IL-9, function to amplify intestinal allergic inflammation and perpetuates anaphylactic response to allergenic dietary proteins. The acquisition of MMC9s may be a key cellular checkpoint for the susceptibility to develop IgE-mediated food allergy.