Marwaha A.K. et al.
Interleukin (IL)-33 is a member of the IL-1 cytokine family and is secreted by fibroblasts, endothelial cells, and epithelial cells in tissues (lung, skin, and gastrointestinal) that are exposed to the environment. 1 IL-33 is stored in the nucleus and environmental allergens trigger RIPK1-caspase 8 ripoptosome activation in epithelial cells to enable IL-33 maturation and release. 2 IL-33 signals via its receptor ST2, which is found on multiple immune cells, such as eosinophils, mast cells, T cells, macrophages, basophils, and type 2 innate lymphoid cells, which all promote type-2 innate immune reactions. 3 Therefore, IL-33 plays a central role in promoting allergic inflammatory responses in diseases such as eosinophilic esophagitis (EoE), allergy to food/inhalants, asthma, and atopic dermatitis. Genome-wide association data of these conditions consistently report polymorphisms in the IL-33 gene as a risk factor. 4 Thus, IL-33 has been proposed as a therapeutic target for these conditions. In animal models, IL-33 has been mechanistically linked with allergic, autoimmune, rheumatologic, and inflammatory bowel diseases. 5 However, monogenic human diseases caused by either gain-of-function or loss-of-function variants in the IL-33 gene have not been reported previously.