Molecular Mechanisms of Eosinophilic Esophagitis

Abstract

Food hypersensitivity is a group of diseases arising from a specific immune response that reproduces on exposure to a given food. The current understanding of molecular mechanisms and immunopathology of non-IgE-mediated/mixed food hypersensitivity, e.g., eosinophilic esophagitis, contains many gaps in knowledge. This review aims to provide a modern classification and identify the primary diseases of non-IgE-mediated/mixed food hypersensitivity reactions, delineate the distinctive molecular features, and discuss recent findings in the immunopathology of eosinophilic esophagitis that may become a basis to develop valid biomarkers and novel therapies for this disease. Eosinophilic esophagitis is a recently recognized allergic-mediated disease with eosinophil-predominant esophagus inflammation. Its pathogenesis is a complicated network of interactions and signaling between epithelial, mesenchymal, and immune cells on molecular and intercellular levels. Alterations produced by overactivation of some cytokine signaling pathways, e.g., IL-13 or thymic stromal lymphopoietin (TSLP), were evolved and observed in this review from the viewpoints of molecular, genetic, epigenetic, and transcriptomic changes. Despite substantial experimental data, the reliable and representative mechanism of eosinophilic esophagitis pathogenesis has yet to show itself. So, the place of esophagitis between mixed and non-IgE-mediated allergic disorders and between eosinophilic gastrointestinal disorders currently seems vague and unclear.

A multi-omic analysis reveals the esophageal dysbiosis as the predominant trait of eosinophilic esophagitis

“…EoE TaMMA confirmed IL13 upregulation in the EoE esophagus by comparison with the control, while IL5, IL4, and the IL13, IL4, and IL5 receptors were not significantly modulated. IL13 was associated with EoE pathogenesis from a clinical standpoint [ 25 , 26 ], and the IL13 signaling inhibition was described as successful in the treatment of this disorder [ 45 ]. In this regard, we can speculate that Dupilumab, a monoclonal antibody against the IL4 receptor, mediating both IL4 and IL13 pathways, was found effective in phase 2 randomized trial of EoE patients [ 45 ] by interfering with the IL13, rather than the IL4 signaling, justifying the absence of statistical significance in the IL4 modulation in our platform.…”

“…IL13 was associated with EoE pathogenesis from a clinical standpoint [ 25 , 26 ], and the IL13 signaling inhibition was described as successful in the treatment of this disorder [ 45 ]. In this regard, we can speculate that Dupilumab, a monoclonal antibody against the IL4 receptor, mediating both IL4 and IL13 pathways, was found effective in phase 2 randomized trial of EoE patients [ 45 ] by interfering with the IL13, rather than the IL4 signaling, justifying the absence of statistical significance in the IL4 modulation in our platform. Further clarifications will come from other transcriptomics studies with larger sample sizes that, once they will be available to the scientific community, will be integrated within the web app to better explain the role of IL4 and IL5 in EoE pathogenesis.…”

White blood cells and chronic rhinosinusitis: a Mendelian randomization study

“…From a mechanistic standpoint in terms of CRS, eosinophils are classically associated with type 2 inflammation that is characterized by elevated levels of IL-4, IL-5, IL-13, and total IgE. This type of eosinophil-associated inflammation has also been well-described in other allergic diseases [ 25 , 26 ]. Despite differing CRS phenotypes distinguished by the presence or absence of nasal polyps, type 2 immune responses are clearly associated with disease severity regardless of phenotype.…”

Blood-Based Biomarkers for Eosinophilic Esophagitis and Concomitant Atopic Diseases: A Look into the Potential of Extracellular Vesicles

“…Sensitized epithelial cells then orchestrate the immunological response by releasing alarmins (IL-25, IL-33, and TSLP) responsible for the polarization of CD4+ T cells towards Th2 phenotype [ 29 , 30 , 31 ]. Cytokines released by Th2 lymphocytes (IL-4, IL-5, and IL-13) stimulate, among others things, the proliferation of eosinophils that are subsequently recruited to the inflammatory foci from circulation, causing the eosinophilia characteristic of EoE, BA, and AD [ 32 , 33 , 34 , 35 ]. The cytotoxic nature of eosinophil-granule proteins released locally then promotes skin lesions and pruritus in AD [ 36 ].…”