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Immune-epithelial networks characterise the cellular ecosystem of the small intestine in celiac disease

ABSTRACT: The immune-epithelial interactions driving intestinal damage in coeliac disease (CD) are incompletely understood.We applied single-cell (scRNA-seq) and spatial transcriptomics to define this. scRNA-seq of 76,824 immune and epithelial cells in 23 subjects with and without CD showed epithelial populations shifted towards a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T-cells showed numeric and functional changes in regulatory, T follicular helper-like CD4+T-cell, natural intraepithelial lymphocytes, and CD8+T-cell subsets with a skewed TCR repertoire.Mucosal changes persisted despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptionally-distinct niches beyond that described in conventional histological scores,including CD-specific lymphoid structures containing localised T-B cell interactions. Spatial transcriptomics-driven receptor-ligand analyses and examination of disease susceptibility gene expression defined networks of altered chemokine and morphogen signalling, which may drive crypt axis distortion andallowed spatial/cellular resolution of where genetic drivers of CD act in tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252545 | GEO | 2025/05/01

REPOSITORIES: GEO

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Project description:Background: The molecular pathogenesis of small intestinal adenocarcinomas (SBA) is not well understood. Defining its molecular pathogenesis may lead us to better clinical interventions. Aim: to identify the molecular changes characteristic of SBA. Methods: Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations, by high resolution array comparative hybridization (aCGH), microsatellite status (MSI) and APC promoter methylation and mutation status. Furthermore, molecular alterations found in CD-related SBA were compared to non-CD related SBA. Results: Chromosomal changes were observed in 77% of the SBA. The most frequently (>10%) DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2 and 20p13-20q13.33 and losses of 4p13-4q35.2, 5q15-5q21.1 and 21p11.2-21q22.11. Seven highly amplified regions on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1 and 19q13.2 were also identified. CD-related and non CD-related SBA displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non CD-related and 73% CD-related SBA. No nonsense mutations were found. Last, 10% of the non CD-related SBA were MSI, whereas 43% of the CD-related SBA were MSI. Conclusions: Our study characterized specific chromosomal aberrations and amplifications involved in SBA pathogenesis. At the chromosomal level, CD-related and non CD-related SBA do not differ. The involvement of the MMR system in the pathogenesis of the CD-related SBA was larger than what has been observed in no CD-related SBA. No nonsense mutations were found in SBA, but frequent promoter methylation in CD-related SBA. Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations against a Human pool, by high resolution array comparative hybridization (aCGH),

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Immune-epithelial networks characterise the cellular ecosystem of the small intestine in celiac disease

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