Rare, Novel Chromosomal Duplication of Entire IL-33 Gene Documented in Case Study

In their paper, the researchers detail the first, to their knowledge, case of a potential gain of function phenotype for IL-33 in a human.

Researchers are sharing their learnings from a patient with a rare, novel chromosomal duplication of a gene that has been shown to promote allergic inflammatory response in certain diseases, such as eosinophilic esophagitis (EoE).

In their paper, the researchers detail the first, to their knowledge, case of a potential gain of function phenotype for IL-33 in a human. The duplication of the gene was revealed when the patient, a boy aged 12 years, underwent genetic testing, which showed a de novo 0.58Mb duplication of unknown significance at chromosome 9p24.1 that encompassed the entire IL-33 gene.

Further testing with whole genome sequencing confirmed the duplication was in tandem. It also revealed that there were no other pathogenic or likely pathogenic variants in other genes responsible for the patient’s phenotype. No similar duplications were detected in the DECIPHER database.

The researchers examined the protein expression of IL-33 in various tissue samples from the skin and gut, revealing differences in subcellular localization of IL-33 that the group said may have implications for the effectiveness of IL-33 targeted treatments across different parts of the body.

“We found a significant elevation of IL-33 protein in the patient’s gastrointestinal biopsy samples compared to 9 healthy controls (P=0.0001) and 9 children with inflammatory bowel disease,” wrote the researchers. “Baseline elevation of IL-33 on immunoflourescence was noted not only in skin biopsies with active eosinophilic mediated inflammation (nuclear localization) but also in non-inflamed gut biopsy samples from the patient (cytoplasmic localization). An increase in IL-33 expression has been shown previously in EoE.”

mRNA sequencing revealed that IL-33 mRNA expression was significantly elevated in the patient’s blood compared with tissue-match samples and with the patient’s parents. The researchers also observed elevation of IL-33 mRNA expression in fibroblast samples from the patient, who exhibited predominantly mucosal, skin, and tissue-based manifestations.

The boy, since infancy, presented with multiple atopic disease manifestations, including EoE, hypereosinophilia, elevated IgE, recurrent eosinophilic skin infiltrations, food allergy, and asthma.

IL-33 is stored in the nucleus and environmental allergens trigger RIPK1-2 caspase 8 ripoptosome activation in epithelial cells to enable IL-33 maturation and release. 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 (ILC2s)—that all
promote type-2 innate immune reactions,” wrote the researchers.

“Therefore, IL-33 plays a central role in promoting allergic inflammatory responses in diseases such as EoE, allergy to food/inhalants, asthma and atopic dermatitis. Genome wide association data of these 4 conditions consistently report polymorphisms in the IL-33 gene as a risk factor,” they said.

The researchers noted that while the patient showed certain features of atopic type 2 mediated response, such as asthma, he did not present with atopic dermatitis but rather an eosinophil-dominated skin inflammation condition.


Marwaha A, Laxer R, Liang M, et al. A chromosomal duplication encompassing IL-33 causes a novel Hyper IgE phenotype characterized by eosinophilic esophagitis and generalized autoimmunity. Gastroenterology. Published online April 27. 2022. doi:10.1053/j.gastro.2022.04.026

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