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

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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.

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Acknowledgements

We thank S. Hottinger for editorial assistance. This work is supported by the National Institutes of Health (R01 AI090129-1, R01 AI112626-01, and 2U19 AI070235-11), Department of Defense (W81XWH-15-1-0517), and the Digestive Health Center of Cincinnati Children’s Hospital Medical Center (P30 DK078392).

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Authors and Affiliations

  1. Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Burnet Avenue, Cincinnati, OH, 45229, USA

    Dana Shik, Sunil Tomar, Andrew Smith & Yui-Hsi Wang

  2. Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, South Korea

    Jee-Boong Lee

  3. Division of Hematology/Oncology and Bone Marrow Transplantation, Nationwide Children’s Hospital, Columbus, 43205, USA

    Chun-Yu Chen

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  1. Dana Shik
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  2. Sunil Tomar
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  3. Jee-Boong Lee
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Correspondence to Yui-Hsi Wang.

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This article is a contribution to the special issue on Th9 Cells in Immunity and Immunopathological Diseases - Guest Editors: Mark Kaplan and Markus Neurath

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Shik, D., Tomar, S., Lee, JB. et al. IL-9-producing cells in the development of IgE-mediated food allergy. Semin Immunopathol 39, 69–77 (2017). https://doi.org/10.1007/s00281-016-0605-x

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