The Role of B Cells and Antibodies in Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood. To investigate the role of epithelial IKKβ/NFκB signaling in EoE pathogenesis using a mouse model with conditional Ikk β knockout in esophageal epithelial cells ( Ikk β EEC-KO ). EoE was induced in Ikkβ EEC-KO mice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes. Ikkβ EEC-KO /EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKβ/NFκB signaling pathways, with decreased expression of RELA and increased expression of IKKβ negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity. Our study demonstrates that loss of epithelial IKKβ signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkβ EEC-KO /EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE. Critical Role of Epithelial IKKβ/NFκB Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health.Molecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE. Relevance of the Ikkβ EEC-KO /EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies. This study reveals the crucial role of epithelial IKKβ/NFκB signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.

Esophageal epithelial Ikkβ deletion promotes eosinophilic esophagitis in experimental allergy mouse model.

Expression of mast cell–associated genes is upregulated in adult eosinophilic esophagitis and responds to steroid or dietary therapy

Eosinophilic esophagitis: New insights into an emerging disease

Expanding the paradigm of eosinophilic esophagitis: Mast cells and IL-9

This Month in Gastroenterology

Anti–TNF-α (infliximab) therapy for severe adult eosinophilic esophagitis

Biologicals Move Into the Esophagus

Role of genetics, environment, and their interactions in the pathogenesis of eosinophilic esophagitis.

Gastroesophageal Reflux Disease–Associated Esophagitis Induces Endogenous Cytokine Production Leading to Motor Abnormalities

Chronic eosinophilic inflammation is associated with tissue remodeling and fibrosis in a number of chronic T-helper 2 (Th2)-mediated diseases including eosinophilic esophagitis (EoE) and asthma. Chronic inflammation results in dysregulated tissue healing, leading to fibrosis and end organ dysfunction, manifesting clinically as irreversible airway obstruction in asthma and as esophageal rigidity, strictures, narrowing, dysmotility, dysphagia, and food impactions in EoE. Current therapies for EoE and asthma center on reducing inflammation-driven tissue remodeling and fibrosis with corticosteroids, coupled with symptomatic control and allergen avoidance. Additional control of Th2 inflammation can be achieved in select asthma patients with biologic therapies such as anti-IL-5 and anti-IL-13 antibodies, which have also been trialed in EoE. Recent molecular analysis suggests an emerging role for structural cell dysfunction, either inherited or acquired, in the pathogenesis and progression of EoE and asthma tissue remodeling. In addition, new data suggest that inflammation-independent end organ rigidity can alter structural cell function. Herein, we review emerging data and concepts for the pathogenesis of tissue remodeling and fibrosis primarily in EoE and relevant pathogenetic parallels in asthma, focusing additionally on emerging disease-specific therapies and the ability of these therapies to reduce tissue remodeling in subsets of patients.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease of the esophagus that exerts a significant clinical and financial burden in developed countries. Despite an emerging interest in this disease, the cellular and molecular mechanisms driving EoE pathogenesis remain elusive. Addressing this knowledge gap is critical to guide the development of novel approaches for diagnosis, monitoring, and therapy in patients with EoE. As EoE is an allergic inflammatory disorder that results in esophageal inflammation and tissue remodeling, in vivo studies are critical to develop a better understanding of this disease. Here, we provide a review of murine models of EoE, highlighting the mechanistic and translational insights into EoE pathogenesis and therapeutic approaches that studies using these models have uncovered. We further discuss the strengths and limitations of EoE mouse models, as well as opportunities for future in vivo approaches to study EoE. Overall, this article reviews the progress, challenges, unmet needs, and opportunities in murine modeling of EoE.

Eructations From Eosinophils

Eosinophilic esophagitis (EoE) and its related subtypes-such as EoE-like esophagitis, lymphocytic esophagitis, and nonspecific esophagitis-pose significant diagnostic challenges due to overlapping clinical, histological, and endoscopic features. Although conventional EoE is well-characterized as a Th2-mediated disorder, the molecular and immunological drivers for its subtypes are poorly understood. We aimed to elucidate the unique molecular signatures underlying these esophageal inflammatory conditions, with the goal of refining disease classification and paving way to targeted therapeutic approaches. We performed an integrative multi-omics analysis incorporating differential gene expression profiling, weighted gene co-expression network analysis (WGCNA), functional enrichment studies, and machine-learning algorithms to identify molecular hallmarks that differentiate EoE from its subtypes. After examining subtype specific alteration in immune and metabolic pathways, novel biomarkers and regulatory mechanisms were uncovered. Conventional EoE exhibited a distinct upregulation of periostin (POSTN), reinforcing extracellular matrix remodeling as its primary pathogenic mechanism. We identified DNAH11 as a key player in epithelial turnover and esophageal dysmotility, revealing its previously unrecognized role in EoE pathogenesis. Suppressed zinc-related pathways (MT1X, MT1F, MT2A) suggest epithelial barrier dysfunction, with differential zinc transporter expression (SLC39A1, SLC39A2) indicating disruptions in zinc homeostasis, which may have therapeutic implications. Additionally, aberrant CDX2 expression linked to methyl-CpG binding proteins suggests an epigenetic contribution to esophageal epithelial remodeling, hinting at metaplasia-like processes in chronic EoE. In contrast, EoE-like esophagitis was primarily immune-driven, marked by CXCR3 ligand activation (CXCL9, CXCL10, CXCL11) and immunoglobulin complex enrichment, indicating systemic immune dysregulation and a potential precursor state to conventional EoE. Lymphocytic esophagitis demonstrated unique signature of metabolic dysfunction, with downregulation of oxidative phosphorylation genes (NDUFB2, ATP5F1B) and enrichment of neuro-immune signaling pathways, pointing at interplay between mitochondrial impairment and esophageal sensory dysfunction. A robust interferon-mediated immune response (STAT1, IRF1 and CXCL10) further differentiated the latter subtype from Th2-driven conventional EoE. Nonspecific esophagitis exhibited a dominant humoral immune response, enriched for immunoglobulin-related pathways, suggestive of a B-cell-driven inflammatory mechanism distinct from the T-cell-dominated responses of other EoE subtypes. This study unveils novel molecular and immunological distinctions between conventional EoE and its subtypes. We propose that EoE-like esophagitis represents an early immune-activated phase, while lymphocytic and nonspecific esophagitis exhibit distinct metabolic and humoral immune dysregulations, respectively. Key biomarkers, POSTN, DNAH11, CDX2, and zinc transporters, offer critical insights for improving diagnostic criteria and guiding therapeutic approaches. These findings highlight the importance of subtype-specific therapeutic interventions and warrant longitudinal studies to map disease trajectories and therapeutic responses across EoE and its variants.

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