Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies.

Expression of Immunoglobulin G4 in Eosinophilic Esophagitis

“…These markers not only aid in diagnosis but also help elucidate the pathogenesis of EoE to guide treatment strategies. The discovery of the effect of dupilumab, which targets IL-4 and IL-13 in the type 2 inflammatory response, is an example of how identifying specific immunological markers can advance the treatment of EoE [31][32][33]. This demonstrates the clinical importance of research to identify accurate immunologic markers for EoE.…”

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties

“…IL-5 promotes the differentiation, maturation, and release of eosinophils from the bone marrow [23], enhances eosinophil trafficking to the esophagus [24] and, in murine models of EoE, drives esophageal fibrous remodeling [25]. Among other functions, IL-4 promotes the differentiation of Th2 lymphocytes, the proliferation and differentiation of B lymphocytes, and is a potent inhibitor of apoptosis, thus playing an important role in the development of atopic diseases [26]. Treatment with dupilumab, which blocks IL-4 receptors I and II, has been shown to be effective in several atopies, including asthma and atopic dermatitis, and also improves histological, endoscopic, and EoE symptoms [27,28].…”

The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs

“…Recurring mediators involved in this inflammatory milieu are, inter alia, IL-4, IL-5, IL-13, eotaxin, and periostin, triggering eosinophil infiltration and mast cell activation [10]. Particularly, eosinophils are the hallmark of the pathogenesis of EoE, releasing cytotoxic proteins and mediators of inflammation, such as eosinophil peroxidase, eosinophil cationic protein, and major binding protein, leading both to tissue damage and esophageal dysmotility due to muscarinic M2 receptors dysfunction [11]. Among all cytokines, IL-5 is the most important for the proliferation, survival, and activation of eosinophils.…”

“…Regarding mast cells, although their concentration in the esophageal mucosa and their release of transforming growth factor β1 (TGF-β1), tryptase, leukotrienes, prostaglandins, and histamine have been proven, the trigger of their activation in EoE is still unknown, likely not to be recognized in IgE. As a result of such inflammation, esophageal mucosa is subject to an increased permeability leading to higher exposure to insulting antigens, thus resulting in a self-perpetuating process [11].…”

“…The pivotal role played by IL-4 and IL-13 released by type 2 cells in target tissues of atopic diseases, such as lung, skin, and gut, is very well-known [22,23]. As regards EoE, IL-4 and IL-13 are involved in favoring the releasing of eotaxin (CCL26) by esophageal epithelial cells, leading to eosinophils recruitment [24], Th2 differentiation, B cell IgG1 and IgE class-switching, and in epithelial to mesenchymal transition with consequent fibrosis [11,25]. Being more abundant than IL-4 in EoE, IL-13 plays a key role in the pathogenesis of EoE [26].…”