Cellular and molecular immunological mechanisms in eosinophilic esophagitis: an updated overview of their clinical implications

Abstract

Eosinophilic esophagitis (EoE) is a pathophysiologically complex disorder driven by distinct, multiple mechanisms involving a large number of cells, molecules, and genes. Associated with food allergy from its initial descriptions, a key role for the Th2-type cytokines IL-5 and IL-13 in recruiting and activating eosinophils has been described. Epithelial cells have been recognized as major effectors in initiating EoE, both through their recruitment of iNKT cells towards the esophageal epithelium, which constitutes a major cytokine source, and through the release of eotaxin-3 and other chemoattractants. Epithelial and mesenchymal-released TSLP is a key regulator for which a connecting role between the adaptive and innate mucosal-associated immune response has been suggested. Finally, activated eosinophil- and mast cell-derived TGF β1 secretion is crucial in EoE-associated tissue remodeling.

Keywords::

• diagnosis
• eosinophilic esophagitis
• eosinophils
• eotaxin-3
• food allergy
• IL-13
• IL-5
• immunopathogenesis
• inflammation
• mast cells
• remodeling
• therapy
• TSLP

Financial & competing interests disclosure

The author had no conflict of interest or affiliation with any of the institutions, organizations or companies that might be mentioned in the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Eosinophilic esophagitis (EoE) is a pathophysiologically complex food allergy-related disorder in which not only eosinophils, but also a large number of cells, molecules and genes are involved. A tissue-specific functional phenotype has been recognized for blood circulating eosinophils in EoE.

• EoE has been associated with a Th2-type inflammatory response that shares common molecular pathways with bronchial asthma and other atopic diseases characterized by IL-5, IL-13 and eotaxins expression.

• The strong genetic load of EoE has facilitated the identification of an EoE characteristic genetic profile, which affects 1% of the human genome and is remarkably conserved across gender, age and allergic status. From this, a PCR-based array molecular diagnostic test has been developed to identify patients with EoE in a fast, objective and mechanistic manner, which may overcome the limitations of histological evaluation.

• A key role for esophageal epithelial cells has been recognized in the past few years; their interaction with the normal microbiota modulates the expression of CXCL16 to recruit T lymphocytes (especially invariant natural killer T cells) toward the esophageal epithelium. IL-13 derived from Th-2 cells induces eotaxin-3 expression in epithelial cells; this chemoattractant then recruits eosinophils from the circulating blood.

• An increasing role for invariant natural killer T cells as the major source of proinflammatory Th2 cytokines in EoE has recently been recognized. These are activated after exposure to glycolipids (including those contained in some common food allergens), and their modulation is proposed as a potential therapeutic target in EoE.

• Epithelial and other mesenchymal cells also produce thymic stromal lymphopoietin, which has been shown to be a key regulating factor in EoE, acting as a link between the mucosa-associated innate immune system and adaptive responses.

• Topical steroids are the most commonly used treatment for EoE patients; their predominant effect over epithelial cells is able to reverse the EoE transcriptome in vitro, repressing the activity of the eotaxin-3 gene promoter induced by IL-13.

• Recognized only a few years ago, PPI-responsive esophageal eosinophilia constitutes a differential diagnosis of EoE. Although considered mutually exclusive disorders, they are indistinguishable in their demographic, clinical, endoscopic and even molecular characteristics. In fact, the effect of PPI drugs in reducing eotaxin-3 gene expression by acting on the gene promoter provides additional proof of the close relationship between both disorders.

• The molecular basis and clinical consequences of esophageal remodeling in EoE have been increasingly recognized in recent years. These complex phenomena appear to be a direct consequence of the Th2 cytokine-promoted tissue eosinophilia and involve mast cells, fibroblasts and smooth muscle cells.

• TGF-β1 released by activated eosinophils and mast cells directly activates epithelial cells and fibroblasts, which transdifferentiate into myofibroblasts capable of synthesizing and depositing extracellular matrix components in an epithelial–mesenchymal transition that leads to tissue remodeling. This phenomenon underlies the symptoms and fibrotic stenosis observed in EoE patients, and its reversibility has not yet been fully demonstrated.

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