Eosinophils in EoE: Barrier Injury, Fibrosis, and Treatment

Key Takeaways

• Across a comprehensive narrative review of eosinophilic esophagitis literature, eosinophils were described as central drivers of epithelial injury, type 2 inflammation, and fibrostenotic remodeling within a broader inflammatory network.
• IL-13-driven CCL26, or eotaxin-3, was described as a key epithelial recruitment signal in EoE and was reported to reach up to 53-fold overexpression in the EoE transcriptome.
• Fibrostenotic burden increased with diagnostic delay in EoE, with stricture prevalence rising from 17.2% at 0-2 years to 70.8% after more than 20 years.
• Anti-IL-5 and anti-IL-5R strategies generally improved histology more than symptoms, and the review suggests persistent dysphagia may reflect ongoing mast-cell activation, epithelial dysfunction, and remodeling.

A Cells review on eosinophils in eosinophilic esophagitis synthesized clinical, translational, and experimental literature on eosinophilic esophagitis (EoE), including eosinophil biology, inflammatory signaling, epithelial remodeling, fibrosis, gastroesophageal reflux disease (GERD) overlap, allergic comorbidities, and therapeutic targets. Across the discussion, the authors traced interactions involving type 2 helper T-cell (Th2) cytokines, thymic stromal lymphopoietin (TSLP), transforming growth factor-beta 1 (TGF-β1), endoscopic Functional Lumen Imaging Probe (EndoFLIP), and the EoE Histologic Scoring System (EoEHSS), moving from recruitment biology to remodeling and then therapy.

In the review, IL-13-driven CCL26, or eotaxin-3, together with IL-4, IL-5, epithelial alarmins, and downstream Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, was described as a central recruitment and activation axis. In active EoE, the authors summarized reduced barrier proteins such as claudins, occludin, zonula occludens-1, E-cadherin, desmoglein-1, involucrin, and filaggrin, along with dilated intercellular spaces, superficial eosinophil accumulation, and eosinophilic microabscesses. They linked fibrostenotic progression to TGF-β1 signaling, SMAD2/3 activation, epithelial-mesenchymal transition, fibroblast activation, extracellular matrix deposition, smooth muscle dysfunction, and eosinophil-derived mediators such as major basic protein, periostin, and matrix metalloproteinase-12. Quantitatively, each additional untreated year was associated with approximately 26% higher odds of stricture, and fibrotic features increased from 46.5% with less than 2 years of diagnostic delay to 87.5% with more than 20 years. Standard endoscopy had 14.7% sensitivity for narrowed esophagus, and pediatric EoE patients aged 9 years and older were described as rigid at an EndoFLIP distensibility index below 4.5 mm2/mmHg. The therapeutic discussion also described a recurring mismatch in which anti-IL-5 and anti-IL-5 receptor therapies reduced tissue eosinophilia more consistently than symptoms, whereas upstream IL-4 and IL-13 blockade was described as affecting multiple disease domains.

As the review emphasized, fibrosis assessment is constrained by sampling depth, with routine esophageal biopsies reaching about 0.5-1 mm in a wall that is roughly 10 mm thick, and only 55% of biopsies including subepithelial tissue. The review noted biopsy-depth and fibrostenosis-definition limitations, and separately described persistent symptoms or remodeling despite eosinophil reduction.

In the authors' overall model, eosinophils remain major regulators and promising biomarkers or therapeutic targets in EoE, but not solitary drivers of disease activity. They instead place eosinophils within a broader network that includes mast cells, Th2 lymphocytes, type 2 innate lymphoid cells (ILC2s), dendritic cells, epithelial alarmins, and stromal remodeling pathways. The discussion also referenced a three-endotype framework derived from a 96-transcript Eosinophilic Esophagitis Diagnostic Panel, adding molecular specificity to the view summarized that EoE is eosinophil-centric without being eosinophil-only.

Clinician Questions

What pathway links epithelial activation to eosinophil recruitment in eosinophilic esophagitis?

The review identifies IL-13-induced CCL26, also called eotaxin-3, as a key epithelial signal for eosinophil recruitment in eosinophilic esophagitis, correlating with disease activity and reaching up to 53-fold overexpression in the EoE transcriptome. IL-4, IL-5, TSLP, IL-33, and IL-25 were also described as amplifying the same type 2 inflammatory cascade.

How is diagnostic delay associated with fibrostenotic disease in eosinophilic esophagitis?

In the reviewed eosinophilic esophagitis literature, stricture prevalence rose from 17.2% at 0-2 years of diagnostic delay to 70.8% after more than 20 years, each additional untreated year was associated with about 26% higher odds of stricture, and fibrotic features increased from 46.5% to 87.5% across the shortest and longest delay categories.

Why can dysphagia persist after histologic eosinophil reduction with anti-IL-5 therapy in EoE?

The authors describe a partial dissociation between tissue eosinophil reduction and symptom relief in eosinophilic esophagitis and suggest that persistent mast cell activity, epithelial barrier dysfunction, and remodeling pathways may contribute even when eosinophils fall. The review included a benralizumab example in which eosinophil counts decreased but dysphagia did not resolve.

What features help distinguish eosinophilic esophagitis from GERD beyond eosinophil counts?

The review describes GERD as usually showing milder distal eosinophilia below 7-10 eos/hpf, whereas current guidelines define eosinophilic esophagitis by at least 15 eos/hpf or 60 eos/mm2 in the appropriate clinical context. Eosinophilic microabscesses, surface layering, degranulation, and subepithelial fibrosis were described as more characteristic of eosinophilic esophagitis, even though histologic overlap can occur.

Recommended Reading

• For more on EoE as a comorbidity: Allergic Comorbidities in Atopic Dermatitis: What the Evidence Shows