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January 2024

Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis

Kleuskens MT, Haasnoot ML, Garssen J et al

The Journal of Allergy and Clinical Immunology 2023 Nov 14

Reviewed by Eva Gruden, Pharmacist, Medical University of Graz, Austria

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease of the esophagus affecting approximately 1 in 3000 people (Muir & Falk, 2021). The etiology of EoE is multifactorial and as of today incompletely understood (Khan et al., 2021). Previous studies have delved into bulk (Sherrill & Rothenberg, 2011) and single cell level (Ben-Baruch Morgenstern et al., 2022; Rochman et al., 2022; T et al., 2019) transcriptomic as well as proteomic (Molina-Jiménez et al., 2023) analysis of active EoE inflammatory profile in mucosal biopsies.

In the current paper the authors focused their efforts on uncovering the acute esophageal transcriptional response of the esophageal epithelium in response to food allergens. A small number of EoE patients were exposed to intramucosal injections of previously reported (clinically suspicious) food allergens as well as three of the most common food allergens. Combining this approach with in vitro assays the authors uncovered that esophageal epithelial cells are potential source of the early dysregulated EoE gene TNFSF18. Interestingly, early upregulation of TNFSF18 in vitro was only observed following a combination treatment with TNF-α and IL-13 and not with each cytokine alone. This has important implications for in vitro assay design, where only one cytokine (predominantly IL-13) is often used to mimic EoE-like pathology.

A major strength of the paper is that the changes were evaluated intra-individually where baseline combined with both negative and positive visual response biopsy area were collected from the same patient. A limitation however lies in the study design, where the epithelial barrier is broken via the injection and antigen delivery is therefore different compared to natural exposure. Additionally, it remains possible that the acute genes, which are induced in only minutes from the antigen injection, may be a non-specific consequence of the procedure rather than truly representing immune hypersensitivity. Examination of non-EoE control patients might be informative. In future analysis of both transcriptomic and proteomic changes following antigen stimulation over time in different allergic entities will provide further understanding of disease pathology and major immune and stromal cell players.

The particular study design of this article enabled the authors to discover TNFSF18 as a candidate gene for further drug development in EoE, thereby joining other atopic conditions like asthma and atopic dermatitis.

Ben-Baruch Morgenstern, N., Ballaban, A. Y., Wen, T., Shoda, T., Caldwell, J. M., Kliewer, K., Felton, J. M., Abonia, J. P., Mukkada, V. A., Putnam, P. E., Bolton, S. M., Dwyer, D. F., Barrett, N. A., & Rothenberg, M. E. (2022). Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission. The Journal of Allergy and Clinical Immunology, 149(6), 2062–2077.

Khan, S., Guo, X., Liu, T., Iqbal, M., Jiang, K., Zhu, L., Chen, X., & Wang, B. M. (2021). An Update on Eosinophilic Esophagitis: Etiological Factors, Coexisting Diseases, and Complications. Digestion, 102(3), 342–356.

Molina-Jiménez, F., Ugalde-Triviño, L., Arias-González, L., Relaño-Rupérez, C., Casabona, S., Pérez-Fernández, M. T., Martín-Domínguez, V., Fernández-Pacheco, J., Laserna-Mendieta, E. J., Muñoz-Hernández, P., Arias-Arias, Á., Cano, A., Muñoz, J., Lucendo, A. J., Santander, C., & Majano, P. (2023). Proteomic analysis of the esophageal epithelium reveals key features of eosinophilic esophagitis pathophysiology. Allergy, 78(10), 2732–2744.

Muir, A., & Falk, G. W. (2021). Eosinophilic Esophagitis: A Review. JAMA, 326(13), 1310–1318.

Rochman, M., Wen, T., Kotliar, M., Dexheimer, P. J., Morgenstern, N. B. B., Caldwell, J. M., Lim, H. W., & Rothenberg, M. E. (2022). Single-cell RNA-Seq of human esophageal epithelium in homeostasis and allergic inflammation. JCI Insight, 7(11).

Sherrill, J. D., & Rothenberg, M. E. (2011). Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies. The Journal of Allergy and Clinical Immunology, 128(1), 23–24.

T, W., BJ, A., Y, R., M, R., K, K., PJ, D., P, P., V, M., H, F., K, R., S, D., D, D., & ME, R. (2019). Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis. The Journal of Clinical Investigation, 129(5), 2014–2028.

Eva Gruden is a pharmacist that completed her PhD at the Medical University of Graz in Austria with distinction. She investigated new ways to target eosinophil overactivation in an interdisciplinary approach. In addition, she completed a stay abroad under the supervision of Dr. Bruce Bochner at Northwestern University in Chicago, where she further deepened her knowledge of complex animal models, monoclonal antibodies and the biology of eosinophils in mice and humans. She is currently a Postdoctoral researcher at the Department of Pharmacology and is studying the involvement of the endocannabinoid and prostaglandin system in EoE.

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