{"doi":"10.64898/2026.03.20.713219","title":"Hidden immune memory niches in inflammatory skin diseases","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Disease-associated histopathological features are widely used to identify tissue microenvironments or niches for diagnostics and treatment response in clinical practice. However, despite its widespread use, histopathology does not reveal the full cellular and molecular composition of known pathological niches. Furthermore, the existence of pathological niches that may not be histologically discernible remains unknown. In this study, we generated a spatially-resolved multi-modal molecular atlas of ∼5 million human skin cells (including 113 skin sections profiled using Xenium-5k) and applied deep learning to unbiasedly decode 26 skin niches in health and disease. Several disease-associated niches corresponded to known histopathological features, and we defined their cellular and molecular features, co-localisations, and interactions. Additionally, we discovered an immunologically active role for skin appendageal structures in disease mechanisms, potentially contributing to inflammatory memory, that was not identifiable using standard histopathological analysis. These include a resident memory T cell-rich niche in the sebaceous gland and a plasma cell-rich niche in the sweat gland, analogous to the gland-associated immune niche in lung. Finally, we illustrate how our atlas can be used to generate high-resolution representations using transfer learning, resolving rare T cell and sebocyte subsets not possible in the original studies, validating niche identification, and the spatial enrichment of candidate genes linked to disease-associated genetic variants. Overall, our study links histopathology and atlas-scale genomics to reveal novel insights into inflammatory disease pathogenesis, chronicity, and potentially curative therapeutic avenues, using skin as an exemplar tissue for this approach.</jats:p>","journal":null,"year":null,"id":654901,"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":1709301,"name":"April R Foster","orcid":null,"position":1,"is_corresponding":false},{"id":65409,"name":"Kenny Roberts","orcid":"0000-0001-6155-0821","position":2,"is_corresponding":false},{"id":990794,"name":"Chloe Admane","orcid":"0009-0005-9327-9008","position":3,"is_corresponding":false},{"id":35657,"name":"Sebastian Birk","orcid":"0009-0005-8854-177X","position":4,"is_corresponding":false},{"id":1709303,"name":"Pavel V Mazin","orcid":null,"position":5,"is_corresponding":false},{"id":1709304,"name":"Amir Akbarnejad","orcid":null,"position":6,"is_corresponding":false},{"id":1205475,"name":"Catherine Tudor","orcid":"0000-0003-2093-9683","position":7,"is_corresponding":false},{"id":1709305,"name":"Benjamin Rumney","orcid":null,"position":8,"is_corresponding":false},{"id":1709306,"name":"Hon Man Chan","orcid":null,"position":9,"is_corresponding":false},{"id":36232,"name":"Bayanne Olabi","orcid":"0000-0002-4786-7838","position":10,"is_corresponding":false},{"id":1709307,"name":"Treasa Jiang","orcid":null,"position":11,"is_corresponding":false},{"id":1709308,"name":"Victoria Rowe","orcid":null,"position":12,"is_corresponding":false},{"id":972853,"name":"David Baudry","orcid":"0000-0003-0784-1286","position":13,"is_corresponding":false},{"id":675269,"name":"Christine Hale","orcid":"0000-0002-3600-4607","position":14,"is_corresponding":false},{"id":95949,"name":"Elena Winheim","orcid":"0000-0002-0364-662X","position":15,"is_corresponding":false},{"id":1709309,"name":"Elias Farr","orcid":"0000-0002-4441-6513","position":16,"is_corresponding":false},{"id":1709310,"name":"Joe McWilliam","orcid":null,"position":17,"is_corresponding":false},{"id":617882,"name":"Laure Gambardella","orcid":"0000-0001-5771-1565","position":18,"is_corresponding":false},{"id":1709311,"name":"Keerthi Priya Chakala","orcid":null,"position":19,"is_corresponding":false},{"id":1709312,"name":"Nusayhah H Gopee","orcid":null,"position":20,"is_corresponding":false},{"id":1709313,"name":"Aljes Binkevich","orcid":null,"position":21,"is_corresponding":false},{"id":1504792,"name":"Alexander Predeus","orcid":null,"position":22,"is_corresponding":false},{"id":52910,"name":"Martin Prete","orcid":"0000-0002-5946-821X","position":23,"is_corresponding":false},{"id":1709314,"name":"Amirhossein Vahidi","orcid":null,"position":24,"is_corresponding":false},{"id":1709315,"name":"Edel A O’Toole","orcid":null,"position":25,"is_corresponding":false},{"id":52877,"name":"Daniela Basurto-Lozada","orcid":"0000-0003-3943-8424","position":26,"is_corresponding":false},{"id":1709316,"name":"David Horsfall","orcid":null,"position":27,"is_corresponding":false},{"id":36233,"name":"Emily Stephenson","orcid":"0000-0002-4244-4019","position":28,"is_corresponding":false},{"id":1709317,"name":"Vijaya Baskar Mahalingam Shanmugiah","orcid":null,"position":29,"is_corresponding":false},{"id":1709318,"name":"Raif S Geha","orcid":null,"position":30,"is_corresponding":false},{"id":104389,"name":"Ramnik J. Xavier","orcid":"0000-0002-5630-5167","position":31,"is_corresponding":false},{"id":572171,"name":"Catherine Smith","orcid":"0000-0001-9918-1144","position":32,"is_corresponding":false},{"id":1709319,"name":"Satveer Mahil","orcid":null,"position":33,"is_corresponding":false},{"id":1694,"name":"Mohammad Lotfollahi","orcid":"0000-0001-6858-7985","position":34,"is_corresponding":false},{"id":11454,"name":"Muzlifah Haniffa","orcid":"0000-0002-3927-2084","position":35,"is_corresponding":false},{"id":1709298,"name":"Lloyd Steele","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Hidden immune memory niches in inflammatory skin diseases","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Disease-associated histopathological features are widely used to identify tissue microenvironments or niches for diagnostics and treatment response in clinical practice. However, despite its widespread use, histopathology does not reveal the full cellular and molecular composition of known pathological niches. Furthermore, the existence of pathological niches that may not be histologically discernible remains unknown. In this study, we generated a spatially-resolved multi-modal molecular atlas of ∼5 million human skin cells (including 113 skin sections profiled using Xenium-5k) and applied deep learning to unbiasedly decode 26 skin niches in health and disease. Several disease-associated niches corresponded to known histopathological features, and we defined their cellular and molecular features, co-localisations, and interactions. Additionally, we discovered an immunologically active role for skin appendageal structures in disease mechanisms, potentially contributing to inflammatory memory, that was not identifiable using standard histopathological analysis. These include a resident memory T cell-rich niche in the sebaceous gland and a plasma cell-rich niche in the sweat gland, analogous to the gland-associated immune niche in lung. Finally, we illustrate how our atlas can be used to generate high-resolution representations using transfer learning, resolving rare T cell and sebocyte subsets not possible in the original studies, validating niche identification, and the spatial enrichment of candidate genes linked to disease-associated genetic variants. Overall, our study links histopathology and atlas-scale genomics to reveal novel insights into inflammatory disease pathogenesis, chronicity, and potentially curative therapeutic avenues, using skin as an exemplar tissue for this approach.</jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41929140","pmcid":null,"openalex_id":"https://openalex.org/W7140189064","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.64898/2026.03.20.713219","host_type":"repository"},{"url":"https://doi.org/10.64898/2026.03.20.713219","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.03.20.713219","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41929140","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13041989/","host_type":"repository"}],"fields_of_study":["Single-cell and spatial transcriptomics","Cutaneous Melanoma Detection and Management","Cell Image Analysis Techniques"],"mesh_terms":[],"keywords":["Histopathology","Niche","Ecological niche","Pathological","Immune system","Disease","Phenome","Phenotype"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T08:50:27.143166Z","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":[]}