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. Plain Language Summary: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the food pipe (esophagus) that causes difficulty swallowing. It is linked to food allergens and has become much more common over the past thirty years, now affecting roughly 1 in every 1,000 people in Western countries. For a long time, doctors believed EoE was caused mainly by one type of immune cell called the eosinophil. We now know the picture is more complex. This review explains that EoE involves many parts of the immune system working together: the lining of the esophagus releases alarm signals that trigger a chain reaction; a group of immune cells called ILC2s amplify this reaction and directly cause thickening of the esophageal wall; and other cells, including mast cells and fibroblasts (which form scar tissue), each play distinct roles in causing symptoms and structural damage. This complexity explains a puzzling observation: several newer treatments that successfully clear the inflammatory cells from the esophagus do not reliably improve swallowing. Our review explains why — because structural damage and nerve sensitization that cause symptoms can persist even after the inflammatory cells are gone.We review three established treatments (acid-suppressing medicines, swallowed steroid preparations, and elimination diets), the first approved targeted therapy (dupilumab, which blocks two key immune signals at once), and a pipeline of newer treatments. We also describe how people with EoE can be grouped into molecular subtypes that may predict which treatment is most likely to help them, moving toward personalized care. The infographic titled ’Immunotargets and Therapy for Eosinophilic Esophagitis’ explores the hidden immune landscape of eosinophilic esophagitis. It features an iceberg metaphor, with eosinophils at the top, associated with IL-5 and IL-5Rα. Below the surface, various immune components are listed: Mast cells linked to Siglec-8 and KIT, ILC2s associated with TSLP, IL-33/ST2 and Areg-EGFR, Fibroblasts connected to TGF-β, LIGHT and TSPAN12 and Sensory neurons related to TRPV1 and the mast cell-neuroimmune axis. This visual representation emphasizes the complexity of immune interactions in eosinophilic esophagitis.Infographic on eosinophilic esophagitis therapy, focusing on immune components and targets. Keywords: eosinophilic esophagitis, type 2 inflammation, ILC2-amphiregulin-EGFR, IL-33/ST2 axis, GPR15, IFN signature, mast cell, neuroimmune, TGF-β, fibrostenosis, dupilumab, precision medicine
Bertin et al. (Fri,) studied this question.