A Chromosomal Duplication Encompassing Interleukin-33 Causes a Novel Hyper IgE Phenotype Characterized by Eosinophilic Esophagitis and Generalized Autoimmunity.

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 Moussion C. et al. PLoS One. 2008; 3: e3331 Crossref PubMed Scopus (887) Google Scholar 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 Brusilovsky M. et al. Nat Immunol. 2021; 22: 1316-1326 Crossref PubMed Scopus (21) Google Scholar 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 Cayrol C. et al. Immunol Rev. 2018; 281: 154-168 Crossref PubMed Scopus (409) Google Scholar 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 Aneas I. et al. Nat Commun. 2021; 12: 6115 Crossref PubMed Scopus (12) Google Scholar 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 Dong Y. et al. Front Med (Lausanne). 2021; 8: 739489 Crossref PubMed Scopus (8) Google Scholar 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.