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TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis
L D Duong1,2, R Rawson1,2, A Bezryadina3
1Division of Allergy & Immunology, University of California, San Diego, San Diego, CA, USA.
Mucosal Immunology
|October 23, 2019
Summary
Eosinophilic esophagitis (EoE) severity may depend on TGFβ1 gene variations. Specific genotypes influence TGFβ1 levels, impacting esophageal remodeling and potentially responding to TGFβ1 inhibition therapy.
Area of Science:
- Immunology
- Gastroenterology
- Genetics
Background:
- Eosinophilic esophagitis (EoE) is a chronic Th2-driven allergic inflammatory disease characterized by tissue remodeling, leading to esophageal dysfunction.
- Transforming growth factor beta 1 (TGFβ1) plays a critical role in driving esophageal remodeling, including epithelial barrier defects and subepithelial fibrosis.
- A common single nucleotide polymorphism (SNP) in the TGFβ1 gene (C-509T) affects its transcription and has been linked to increased TGFβ1 levels in EoE.
Purpose of the Study:
- To investigate the impact of TGFβ1 genetic variations on esophageal fibroblast and epithelial cell function in children with EoE.
- To determine how TGFβ1 influences in vivo and in vitro cellular responses relevant to EoE pathogenesis.
- To explore the potential of TGFβ1-targeted therapies for EoE.
Main Methods:
- Analysis of esophageal biopsies and primary fibroblasts from EoE children with different TGFβ1 C-509T genotypes (TT vs. CC).
- Assessment of gene expression (TGFβ1, collagen1α1, periostin, MMP2), fibroblast contractile properties, and epithelial barrier function (transepithelial resistance, E-cadherin localization).
- In vitro exposure of cells and spheroids to TGFβ1 and treatment with a TGFβ1-receptor-I inhibitor.
Main Results:
- TT-genotype EoE fibroblasts exhibited higher baseline expression of TGFβ1, collagen1α1, periostin, and MMP2, along with distinct contractile properties compared to CC-genotype fibroblasts.
- TGFβ1 exposure induced greater target gene expression in CC fibroblasts in vitro, while TT-genotype esophageal biopsies showed reduced E-cadherin expression and altered distribution.
- TGFβ1 treatment disrupted epithelial barrier integrity and E-cadherin localization in primary human esophageal epithelial cells; a TGFβ1-receptor-I inhibitor partially restored E-cadherin localization.
Conclusions:
- EoE severity and pathogenesis may be influenced by genotypic variations in TGFβ1, affecting in vivo TGFβ1 exposure and cellular responses.
- TGFβ1 signaling is a key mediator of epithelial barrier dysfunction and fibrosis in EoE.
- Targeting TGFβ1 signaling represents a potential therapeutic strategy for specific patient subsets with EoE.
