The Immune Architecture of Eosinophilic Esophagitis: Mechanisms, Therapeutic Targets, and Precision Management

Background:Eosinophilic esophagitis (EoE) is a chronic, allergen-driven, type 2 immune-mediated disease of the esophagus defined by symptoms of esophageal dysfunction and eosinophil-predominant mucosal inflammation (≥15 eosinophils per high-power field), with a rising global prevalence now exceeding 1 in 1,000 individuals in Western countries. Its pathogenesis extends far beyond eosinophils, encompassing epithelial alarmin signaling (TSLP, IL-33, IL-18), ILC2 and Th2 immune activation, and a convergent effector network of eosinophils, mast cells, and fibroblasts that drives barrier disruption and progressive fibrostenotic remodeling. Purpose:This narrative review synthesizes current evidence on the multi-layered immunopathogenesis of EoE, the evolving conceptualization of disease remission, established and emerging therapeutic options, and precision medicine strategies incorporating phenotypic and molecular endotype classification. Key Findings:EoE shares a pathophysiologic continuum with other atopic diseases, underpinned by convergent type 2 immune mechanisms and epithelial barrier gene defects. A recently characterized ILC2-amphiregulin-EGFR axis directly drives structural esophageal remodeling independent of eosinophil recruitment, providing a mechanistic explanation for the histology-symptom dissociation that limits several biologic therapies. First-line therapies-proton pump inhibitors (PPIs), swallowed topical corticosteroids (STCs), and dietary elimination-achieve histologic remission in 45-90% of patients. Dupilumab, the first approved biologic, achieves histologic remission in approximately 59-60% of patients versus 5-6% with placebo at week 24. An expanding pipeline targets IL-13, IL-5R, TSLP, mast cells, and JAK-STAT pathways alongside optimized steroid formulations and oral small molecules. Conclusion:EoE is entering an era of precision therapeutics. Integrating molecular endotyping, multi-effector immunopathology, and multidimensional disease activity assessment will be essential to optimize long-term outcomes, prevent fibrostenotic progression, and individualize the expanding armamentarium of targeted therapies.