Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

Abstract

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.

The Gut Microbiome and Its Implication in the Mucosal Digestive Disorders

“…Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder affecting the esophagus. Characterized by eosinophil-predominant inflammation, Eoe is mediated by type 2 helper T (Th2) cell activity, primarily triggered by food antigens [ 45 ]. The EoE activity seems not to directly affect the bacteria load of the esophageal mucosa but it is associated with changes in microbiota diversity.…”

“…seem to increase its amount [ 50 , 52 ]. Lactococcus lactis NCC 2287 , an inducer of IL-10 immunomodulatory cytokine and an inhibitor of IL-5, a cytokine affecting the survival of eosinophils, has shown its capacity to improve clinical scores in a food allergy model when used as treatment [ 45 ]. Bifidobacterium lactis NCC 2818 was also tested for its capacity to decrease esophageal inflammation in a EoE murine model but its effects were weaker than those obtained after L. lactis NCC 2287 administration.…”

Eosinophils in the Gastrointestinal Tract: Key Contributors to Neuro-Immune Crosstalk and Potential Implications in Disorders of Brain-Gut Interaction

“…In EoE, eosinophil-derived mediators have been shown to target esophageal epithelial integrity. More specifically, IL-13 down-regulates the intercellular adhesion molecule desmoglein-1, but not desmoglein-3, leading to altered epithelial barrier function and the promotion of inflammatory responses [33,34]. Eosinophils also modulate the secretion of mucus and bactericidal substances contributing to the reinforcement of epithelial barrier protection against infection.…”

Therapeutical Targets in Allergic Inflammation

“…Allergic inflammation is crucial in the recruitment of eosinophils to the esophagus; in fact, IL-13 is over-expressed in biopsy specimens obtained from these patients [ 116 , 117 ]. Similarly to other atopic diseases, different endotypes have been identified in eosinophilic esophagitis [ 118 , 119 , 120 ].…”