EE is a chronic disease with less than 10% of the population developing tolerance to their food allergies. EE does not progress into other gastrointestinal diseases.
Eosinophilic esophagitis (EoE) is a polygenic disorder characterized by the accumulation of eosinophils in the esophagus. We carried out a genome-wide association study on clinically and biopsy confirmed EoE patients to identify common variants associated with the disease risk. One hundred and eighty one EoE samples from Cincinnati Children’s Hospital (CCHMC) and 170 EoE samples and ~3100 controls from Children’s Hospital of Philadelphia (CHOP) were genotyped on the Illumina 550K BeadChip. All patients and controls were of European ancestry. Following standard quality control filtering of the genotype data we carried out Cochran-Armitage trend tests at each SNP using the CCHMC samples as a discovery cohort. We detected genome-wide association with variants on chr5q22 that mapped to a single LD block encompassing the TSLP and WDR36 genes. The most significantly associated SNP at that locus which maps upstream of the TSLP gene remained wide significant after Bonferroni correction (rs3806932, uncorrected P-value = 7.18×10−8, OR = 0.54). Eleven other SNPs in LD with rs3806932 were also significantly associated with EoE and mapped to the same LD block on 5q22. We subsequently replicated the association in the independent CHOP cohort (170 cases, 1130 controls) with rs3806932 P-value = 8×10−3 OR = 0.73; combined P-value for rs3806932 across CCHMC and CHOP cohorts = 3.19×10−9). In addition, TSLP was overexpressed in the esophagus of EoE patients compared with control individuals with no differences observed in the expression of WDR36. In conclusion, we have identified the first genetic association with EoE predisposition at 5q22 implicating TSLP and/or WDR36 as genes potentially involved in the pathogenesis of EoE.
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.
Summary Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P ≤ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P ≤ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P ≤ 0.024 and DIS P ≤ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.
Background Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disorder that responds to dietary therapy; however, data evaluating the effectiveness of dietary therapeutic strategies is limited. Objective This study compared the effectiveness of three frequently prescribed dietary therapies [elemental, six-food elimination, and skin prick and atopy patch-directed elimination] and assessed the remission predictability of skin tests and their utility in directing dietary planning. Methods A retrospective cohort of proton-pump inhibitor-unresponsive, non-glucocorticoid-treated eosinophilic esophagitis patients who had two consecutive endoscopic biopsies associated with dietary intervention was identified. Biopsy histology and remissions (< 15 eosinophils/high-power field) following dietary therapy and food reintroductions were evaluated. Results Ninety-eight of 513 patients met eligibility criteria. Of these 98, 50% (49), 27% (26), and 23% (23) received elemental, six-food elimination, and directed diets, respectively. Remission occurred in 96%, 81%, and 65% of patients on elemental, six-food elimination, and directed diets, respectively. The odds of post-diet remission vs. non-remission were 5.6-fold higher (P=0.05) on elemental vs. six-food elimination, 12.5-fold higher (P=0.003) on elemental vs. directed, and were not significantly different (P=0.22) on six-food elimination vs. directed diets. Following 116 single-food reintroductions, the negative predictive value of skin testing for remission was 40%–67% (milk 40%, egg 56%, soy 64%, and wheat 67%). Conclusion All three dietary therapies are effective; however, an elemental diet is superior at inducing histologic remission compared with six-food elimination and skin test-directed diets. Notably, an empiric six-food elimination diet is as effective as a skin test-directed diet. The negative predictive values of foods most commonly reintroduced in single-food challenges are not sufficient to support the development of dietary advancement plans solely based on skin tests.
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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