Breaking down the complex pathophysiology of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated disease of the esophagus associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Our understanding of EoE pathophysiology has evolved since its initial recognition more than 20 years ago and has translated into diagnostic and novel therapeutic approaches that are affecting patient care. The mechanisms underlying disease development and progression are influenced by diverse factors, such as genetics, age, allergic comorbidities, and allergen exposures. Central to EoE pathophysiology is a dysregulated feed-forward cycle that develops between the esophageal epithelium and the immune system. Allergen-induced, type 2-biased immune activation by the esophageal epithelium propagates a cycle of impaired mucosal barrier integrity and allergic inflammation, eventually leading to tissue remodeling and progressive organ dysfunction. Herein, we review the current understanding of fundamental pathophysiological mechanisms contributing to EoE pathogenesis.

Figure 1.

EoE is an allergen-driven, chronic inflammatory disease of the esophagus. Impaired epithelial barrier function and dysregulated immune cell responses influenced by genetic polymorphisms are central to EoE pathogenesis, generating a feed-forward cycle leading to loss of immunologic tolerance to exogenous allergens and chronic eosinophilic inflammation. Created with BioRender.com. EoE, eosinophilic esophagitis; HPF, high-power field; IL, interleukin; T_H2, T helper 2 cells; TSLP, thymic stromal lymphopoietin.

Figure 2.

EoE pathophysiology model. Exogenous allergens trigger epithelial-derived cytokine TSLP and IL-33 production, the latter through activating the intracellular allergen sensor RIPK1-caspase-8 ripoptosome. An impaired mucosal barrier from dysregulated endogenous proteases and an abnormal epithelium allow translocation of food antigens to the dendritic cells, which process and present them to the CD4+ T cells. TSLP and IL-33 influence the dendritic cells to mature T_H2-biased effector T cells and stimulate ILC2s; both populations secrete cytokines IL-4, IL-5, and IL-13, which recruit and activate mast cells, eosinophils, and basophils. Mast cells and eosinophils propagate allergic inflammation through cytokine and inflammatory mediator production (eg, PGD2, leukotrienes, granule enzymes), leading to immune cell activation and epithelial changes that further impair barrier function. A feed-forward cycle develops, causing chronic inflammation that stimulates tissue remodeling/fibrosis through the cytokine TGF-β, epithelial-mesenchymal transition, and pro- and anti-fibrotic mediator (TSPAN-12, TSP1) modulation. Created with BioRender.com. EoE, eosinophilic esophagitis; IL, interleukin; ILC2, type 2 innate lymphoid cell; PGD2, prostaglandin D2; TGF-β, transforming growth factor beta; T_H2, T helper 2 cells; TSLP, thymic stromal lymphopoietin.