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Eosinophilic esophagitis (EoE) is a complex, polygenic disorder.
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Disease risk variants and an altered esophageal transcriptional profile underlie the genetic origin of EoE.
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Emerging epigenetic modifications link environmental exposures to the genetic dysregulation in EoE.
Genetic and Epigenetic Underpinnings of Eosinophilic Esophagitis
Section snippets
Key points
Genetic variants
Several candidate gene approaches have identified a handful of genetic risk variants in EoE. For instance, a common single-nucleotide variant (minor allele frequency [MAF] = 0.25 in the HapMap15 population of European descent) located in the 3′ untranslated region of the chemokine (C-C motif) ligand 26 (CCL26) was overrepresented in patients with EoE in both a case-control and a family-based analysis.4 Furthermore, 2 coding variants (R501X and 2282del4) in the epidermal barrier gene filaggrin (
The EoE transcriptome
A total of 574 highly dysregulated esophageal genes were identified, termed the EoE transcriptome, which distinguishes patients with EoE from healthy controls and, importantly, from patients with noneosinophilic forms of esophagitis.4 Despite the patchiness of EoE and phenotypic diversity within the patients analyzed with EoE, the EoE transcriptome is surprisingly well conserved across patient age, gender, atopic status, and nonfamilial relationship.4, 25 A large-scale screen based on 94
Epigenetics
Epigenetics are the heritable phenotypic modifications that result from gene activation or repression through mechanisms that are independent of changes to the DNA sequence.47 Capable of being influenced by environmental stimuli, the epigenome lies at the crossroads of gene-environment interactions, placing it at the forefront for studying mechanisms underlying environmentally driven allergic inflammatory diseases. This article discusses in detail the current view of epigenetic regulation
Summary
In summary, gene expression profiling of patient tissue and screening for disease risk variants have taken unbiased approaches to reveal many of the critical molecular pathways underlying EoE pathogenesis. Although these pathways continue to undergo rigorous investigation, new research into the epigenetic modification of immunoregulatory genes such as CCL26 and a dysregulated miRNA signature in EoE add additional layers to the molecular entities governing the transcriptome of the inflamed
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Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission
2022, Journal of Allergy and Clinical ImmunologyCitation Excerpt :In active EoE, MCs expressed several additional inflammatory mediators, including IL5, potentially allowing them to interact with eosinophils, and CSF1, potentially allowing them to interact with CSF1R-expressing myeloid cells, an essential interaction for myeloid differentiation and expansion47,48 (Fig E3, B). MCs also expressed TGFB1, suggesting interaction with TGFBR2-expressing fibroblasts, which has the potential to promote fibroblast proliferation and collagen production49 and contribute to the Mendelian-inherited form of EoE caused by TGFBR2 mutations (Fig 3, B).50 MCs also expressed elevated LIF, allowing possible interactions with endothelial cells that express LIFR, a receptor that regulates angiogenesis.51–53
Eosinophilic Esophagitis: Incidence, Diagnosis, Management, and Future Directions
2021, Gastroenterology Clinics of North AmericaCitation Excerpt :A PEC of 15 eos/HPF has 100% sensitivity in detecting EoE and specificity of 96%.41 There is concern, however, that reliance solely on esophageal density may miss other important indicators of disease severity such as barrier dysfunction and esophageal remodeling.7–9 The EoE Histologic Scoring System (EoEHSS) was developed as a quantitative tool to measure efficacy in clinical practice and pharmacologic trials.
Pathomechanisms of eosinophilic esophagitis and the therapeutic implications
2019, Revue Francaise d'AllergologieEpithelial origin of eosinophilic esophagitis
2018, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Indeed, expression of several epithelial genes involved directly in the pathogenesis of EoE is under epigenetic regulation. These genes include CCL26, neurotrophic receptor tyrosine kinase 1 (NTRK1), SYNPO, and CAPN14.57,98-100 In the case of CAPN14, the EoE risk variant rs76562819 is localized in the peak of histone H3 lysine 27 acetylation, which is dynamically regulated by IL-13 stimulation.
Is eosinophilic esophagitis an equivalent of pollen allergic asthma? Analysis of biopsies and therapy guided by component resolved diagnosis
2018, Allergologia et ImmunopathologiaRole of Endoscopy in Diagnosis and Management of Pediatric Eosinophilic Esophagitis
2016, Gastrointestinal Endoscopy Clinics of North AmericaCitation Excerpt :Levels of eosinophil-derived neurotoxin have been shown to be significantly increased in the serum of patients with active EoE but not in stool samples.70 A specific serum micro-RNA (miRNA) signature pattern including induction of miR-21 and miR-223, and repression of miR-375 has been associated with EoE and is distinct from healthy control patients and those with noneosinophilic forms of esophagitis.71,72 Furthermore, this signature nearly completely reverts to normal on disease remission.71,72