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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.

SUBMITTER: Zhernov YV

PROVIDER: S-EPMC8703627 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

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Molecular Mechanisms of Eosinophilic Esophagitis.

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