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 skin to the gut. IL-4 and crosslinking 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.

Oral immunotherapy for food allergy

“…IL-25 stimulates type 2 innate lymphoid cells (ILC2) and drives ILC2 production of the inflammatory cytokine IL-13 [36,37]. With TSLP, IL-25 promotes the development of T helper 9 cells (Th9) which produce IL-9 [38–41], which in turn prompts the accumulation and activation of mast cells [42]. IL-33 contributes to ILC2 expansion and production of the inflammatory cytokine IL-4 [43].…”

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders

“…Though, early in life and in pathological conditions the gastrointestinal mucosal barrier is in an immature state or leaky, respectively, leading to higher exposure to food antigens. While this might be meant to allow establishment of oral tolerance in the first case, it may also result in immune activation and development of food allergy . If this is the case, in a first step of antigen sensitization antigen‐specific Th2 cells secreting high levels of IL‐4, IL‐5, and IL‐13 are primed by DCs in the GALT, which will be discussed in greater detail below.…”

Th9 cells in immunity and immunopathological diseases

“…As discussed above Licona-Limón and colleagues [4], Th9 cells play a role in type 2 immunity, combining functions with Th2 cells in the elimination of extracellular parasites. However, Th9 cells also contribute to allergic inflammation in a number of atopic disease states including atopic dermatitis, discussed above by Clark and Schlapbach [6], asthma reviewed by Koch and colleagues [7], and food allergy that is discussed in the article by Wang and colleagues [8]. Koch, Sopel, and Finotto [7] provide a thorough and extensive review of the evidence for a pathological role of Th9 cells in allergic asthma.…”

“…Wang et al [8] describe the role of IL-9-producing cells in food allergy. The authors present background on the clinical manifestations of food allergy and discuss the immune processes, including the balance between tolerance and sensitization to food allergens that are required for food allergy to develop.…”