{"doi":"10.1101/2025.03.05.641653","title":"Immune signaling mediates stromal changes to support epithelial reprogramming in Celiac duodenum","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8\n                  <jats:sup>pos</jats:sup>\n                  , γδ T cells and IFNG transcriptional shifts) and T\n                  <jats:sub>fh</jats:sub>\n                  -related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1β. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1β signal and lymphoid-derived IFN-γ. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.\n                </jats:p>","journal":null,"year":null,"id":640899,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1665939,"name":"Klebea Sohn","orcid":null,"position":1,"is_corresponding":false},{"id":805183,"name":"Shrikanth Chomanahalli Basavarajappa","orcid":"0000-0003-3550-8595","position":2,"is_corresponding":false},{"id":1665941,"name":"Daniel Horowitz","orcid":null,"position":3,"is_corresponding":false},{"id":1665942,"name":"Joshua Rusbuldt","orcid":null,"position":4,"is_corresponding":false},{"id":1665944,"name":"Lynn Tomsho","orcid":null,"position":5,"is_corresponding":false},{"id":1665946,"name":"Kate Paget","orcid":null,"position":6,"is_corresponding":false},{"id":228978,"name":"Ivan Chavez","orcid":"0000-0002-4840-9310","position":7,"is_corresponding":false},{"id":108095,"name":"Koen Van den Berge","orcid":"0000-0002-1833-8478","position":8,"is_corresponding":false},{"id":1665948,"name":"Brad McRae","orcid":null,"position":9,"is_corresponding":false},{"id":1665951,"name":"Heather Loughnane","orcid":null,"position":10,"is_corresponding":false},{"id":1512874,"name":"Seamus Hussey","orcid":null,"position":11,"is_corresponding":false},{"id":717804,"name":"Patrick Walsh","orcid":"0000-0002-2778-9019","position":12,"is_corresponding":false},{"id":1665954,"name":"Darren Ruane","orcid":"0000-0002-1053-2313","position":13,"is_corresponding":false},{"id":228499,"name":"Dylan Richards","orcid":"0000-0002-5823-0859","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Immune signaling mediates stromal changes to support epithelial reprogramming in Celiac duodenum","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8\n                  <jats:sup>pos</jats:sup>\n                  , γδ T cells and IFNG transcriptional shifts) and T\n                  <jats:sub>fh</jats:sub>\n                  -related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1β. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1β signal and lymphoid-derived IFN-γ. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.\n                </jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W4408314698","authors":[],"funders":[{"funder_name":"Our Lady's Children's Hospital, Crumlin","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Science Foundation Ireland","grant_id":"21/FFP-P/10135","title":"Identifying the mechanism of action of a novel therapeutic target  during the earliest phases of IBD onset in childhood."}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/03/10/2025.03.05.641653.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/03/10/2025.03.05.641653.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.03.05.641653","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.03.05.641653","host_type":"repository"},{"url":"https://doi.org/10.2139/ssrn.5202572","host_type":""},{"url":"https://doi.org/10.1016/j.celrep.2025.116039","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/40694474","host_type":""},{"url":"https://doaj.org/article/61b42177acae4b67a31d7092210b0c98","host_type":""}],"fields_of_study":["Digestive system and related health","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":[],"keywords":["Duodenum","Immune system","Reprogramming","Stromal cell","Cell biology","Biology","Immunology","Cancer research","Medicine","Internal medicine","Cell","Genetics","Male","QH301-705.5","CP: Immunology","Epithelial Cells","Cell Communication","Fibroblasts","Cellular Reprogramming","Celiac Disease","Interferon-gamma","Humans","Female","Biology (General)","Stromal Cells","Intestinal Mucosa","Signal Transduction"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T14:20:59.254414Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}