Dataset Information

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

ABSTRACT: Clinical benefits of cytokine blockade in ileal Crohn’s disease (iCD) are limited to a subset of patients. Here we applied single cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct connectivity network that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in 4 independent iCD cohorts (n=441), and its presence at diagnosis correlated with failure to achieve corticosteroid-free durable remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities

ORGANISM(S): Homo sapiens

PROVIDER: GSE134809 | GEO | 2019/08/29

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:The incidence of inflammatory bowel disease, including Crohn’s disease (CD), continues to increase worldwide, however, the contribution of CD4+ cell populations remains to be elucidated. Emerging evidence suggested increased infiltration of potentially dysfunctional FOXP3+ regulatory T (Treg) cells in inflammatory lesions. In this study, we aimed to provide an in-depth transcriptional assessment of CD4+ cells driving chronic ileal inflammation. For this purpose, ileal biopsies were isolated from five CD patients as well as six healthy individuals and CD4+ cells were purified for subsequent single cell RNA-sequencing (scRNA-seq). Our data revealed the presence of five distinct Treg subpopulations and that Tregs isolated from healthy control subjects represent the origin of pseudotemporal development into inflammation-associated subtypes. These pro-inflammatory Tregs isolated from CD patients displayed a unique responsiveness to TNFα signaling resulting in the upregulation of Treg-specific genes induced in Crohn’s (TRICs). We were able to establish an in vitro model of these pro-inflammatory FOXP3-positive cells which displayed an upregulation of TRICs, impaired suppressive activity as well as an elevated cytokine response in a novel organoid co-culture system. Intriguingly, based on our scRNA-seq data, an in silico drug prediction tool identified the histone deacetylase (HDAC) inhibitor (HDACi) Vorinostat as a putative regulator of the gene expression patterns from CD Tregs compared to control Tregs. Indeed, Vorinostat treatment resulted in a normalization of gene expression patterns and rescued the suppressive function of FOXP3-positive cells in vitro. Together, we provide insight into the role of CD4+ cells in CD lesions and have demonstrate a pathophysiologic role for TNFα-exposed Treg cells, underlying transcriptome-wide changes as well as potential novel therapeutic approaches. The incidence of inflammatory bowel disease, including Crohn’s disease (CD), continues to increase worldwide, however, the contribution of CD4+ cell populations remains to be elucidated. Emerging evidence suggested increased infiltration of potentially dysfunctional FOXP3+ regulatory T (Treg) cells in inflammatory lesions. In this study, we aimed to provide an in-depth transcriptional assessment of CD4+ cells driving chronic ileal inflammation. For this purpose, ileal biopsies were isolated from five CD patients as well as six healthy individuals and CD4+ cells were purified for subsequent single cell RNA-sequencing (scRNA-seq). Our data revealed the presence of five distinct Treg subpopulations and that Tregs isolated from healthy control subjects represent the origin of pseudotemporal development into inflammation-associated subtypes. These pro-inflammatory Tregs isolated from CD patients displayed a unique responsiveness to TNFα signaling resulting in the upregulation of Treg-specific genes induced in Crohn’s (TRICs). We were able to establish an in vitro model of these pro-inflammatory FOXP3-positive cells which displayed an upregulation of TRICs, impaired suppressive activity as well as an elevated cytokine response in a novel organoid co-culture system. Intriguingly, based on our scRNA-seq data, an in silico drug prediction tool identified the histone deacetylase (HDAC) inhibitor (HDACi) Vorinostat as a putative regulator of the gene expression patterns from CD Tregs compared to control Tregs. Indeed, Vorinostat treatment resulted in a normalization of gene expression patterns and rescued the suppressive function of FOXP3-positive cells in vitro. Together, we provide insight into the role of CD4+ cells in CD lesions and have demonstrate a pathophysiologic role for TNFα-exposed Treg cells, underlying transcriptome-wide changes as well as potential novel therapeutic approaches.

Dataset Information

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure