We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13–driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. Herein, we compared epithelial responses between normal (NL) and EE patients aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained up to 5 passages, with 67% and 62% of cell lines reaching confluence in NL and EE, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 ± 1.98 ng/mL vs. 12.46 ± 2.90 ng/mL at pH 7.4 and 4 respectively, p<0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin, and SPRR3 were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies compared to NL. While the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared to control individuals (6.1% vs. 1.3% respectively, p=0.0172), the decreased filaggrin expression was uniformly seen in all EE patients in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.
Background & Aims Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Herein, we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), currently diagnosed by histology and clinical symptoms. Methods We developed an EoE diagnostic panel (EDP), comprising a 96-gene quantitative PCR array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction, using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14), subsequently vetted using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed paraffin embedded (FFPE) tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. Results The EDP identified adult and pediatric patients with EoE with ~96% sensitivity and ~98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with FFPE tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse following treatment. Conclusions We developed a molecular diagnostic test (referred as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.
Background Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. Objective Early studies have suggested that esophageal eosinophilia occurs in association with T helper type 2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized. Methods A human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays were used to quantify cytokine mRNA in esophageal biopsies and blood levels. Results Esophageal transcripts of numerous chemokines [e.g. CCL1, CCL23, CCL26 (eotaxin-3), CXCL1, and CXCL2], cytokines (e.g. IL13 and ABCF1), and cytokine receptors (e.g. IL5RA) were induced at least 4-fold in individuals with EE. Analysis of esophageal biopsies (n=288) revealed that eotaxin-3 mRNA level alone had 89% sensitivity for distinguishing EE from non-EE individuals. The presence of allergy was associated with significantly increased esophageal expression of IL4 and IL5 mRNA in active EE patients. We identified 8 cytokines (IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40L, IL-1α, and IL-17) whose blood levels retrospectively distinguished 12 non-EE from 13 EE patients with 100% specificity and 100% sensitivity. When applied to a blinded, prospectively recruited group of 36 patients, the cytokine panel scoring system had a 79% positive predictive value, 68% negative predictive value, 61% sensitivity, and 83% specificity for identifying EE. Conclusion Evidence is presented that IL13 and IL5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive Th2 immunity in regulating eotaxin-3-driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines.
Background-The genetic etiology of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of
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