{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:41:14Z","timestamp":1791859274691,"version":"4.3.4"},"reference-count":67,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"NIAMS","doi-asserted-by":"crossref","award":["P50AR060780"],"award-info":[{"award-number":["P50AR060780"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,8]]},"abstract":"<jats:p>Using transcriptomic profiling at single-cell resolution, we investigated cell-intrinsic and cell-extrinsic signatures associated with pathogenesis and inflammation-driven fibrosis in both adult and pediatric patients with localized scleroderma (LS). We performed single-cell RNA-Seq on adult and pediatric patients with LS and healthy controls. We then analyzed the single-cell RNA-Seq data using an interpretable factor analysis machine learning framework, significant latent factor interaction discovery and exploration (SLIDE), which moves beyond predictive biomarkers to infer latent factors underlying LS pathophysiology. SLIDE is a recently developed latent factor regression-based framework that comes with rigorous statistical guarantees regarding identifiability of the latent factors, corresponding inference, and FDR control. We found distinct differences in the characteristics and complexity in the molecular signatures between adult and pediatric LS. SLIDE identified cell type\u2013specific determinants of LS associated with age and severity and revealed insights into signaling mechanisms shared between LS and systemic sclerosis (SSc), as well as differences in onset of the disease in the pediatric compared with adult population. Our analyses recapitulate known drivers of LS pathology and identify cellular signaling modules that stratify LS subtypes and define a shared signaling axis with SSc.<\/jats:p>","DOI":"10.1172\/jci.insight.185758","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T14:04:17Z","timestamp":1744034657000},"source":"Crossref","is-referenced-by-count":10,"title":["Unique and shared transcriptomic signatures underlying localized scleroderma pathogenesis identified using interpretable machine learning"],"prefix":"10.1172","volume":"10","author":[{"given":"Aaron BI","family":"Rosen","sequence":"first","affiliation":[{"name":"Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwesha","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Hutchins","sequence":"additional","affiliation":[{"name":"Department of Pediatrics; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giffin","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Berkowitz","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Tabib","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9398-5034","authenticated-orcid":true,"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Jacobe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Texas Southwestern, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5747-064X","authenticated-orcid":true,"given":"Jishnu","family":"Das","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn S.","family":"Torok","sequence":"additional","affiliation":[{"name":"Department of Pediatrics; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab238"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38853"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kei251"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1177\/0883073820931253"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/art.38814"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2013.4207"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080098"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.5114\/aoms.2012.32421"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.5114\/pdia.2015.48044"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2015.06.006"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/ar4378"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.09.025"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/art.41758"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2023.02.036"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2016.12.020"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.04.008"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24129796"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24607-6"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/art.41813"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/art.42536"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02175-z"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224184"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2023.04.010"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2020.5809"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.081284"},{"issue":"1","key":"B26","first-page":"84","article-title":"The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis","volume":"25","author":"Furst","year":"1998","journal-title":"J Rheumatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/exd.12773"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/art.27220"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/art.39287"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken370"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/cimb46080508"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00874-1"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2022.103344"},{"key":"B34","doi-asserted-by":"crossref","unstructured":"Salih MM, et al. The RNA binding protein, HNRNPA2B1, regulates IFNG signaling in macrophages [preprint]. https:\/\/doi.org\/10.1101\/2023.10.12.562050 Posted on bioRxiv October 15, 2023","DOI":"10.1101\/2023.10.12.562050"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.15811"},{"issue":"7","key":"B36","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1002\/art.41659","article-title":"Dysfunctional keratinocytes increase dermal inflammation in systemic sclerosis: results from studies using tissue-engineered scleroderma epidermis","volume":"73","author":"Russo","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.07.014"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2006.01151.x"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-35840-y"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27117"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1149499"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-023-01191-1"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-017-1106-7"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00233.2002"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.11.7678"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.206"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2024.01.002"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.306534"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002065"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.669116"},{"issue":"127","key":"B51","first-page":"235","article-title":"S100A1 promotes cell proliferation and migration and is associated with lymph node metastasis in ovarian cancer","volume":"23","author":"Tian","year":"2017","journal-title":"Discov Med"},{"issue":"733","key":"B52","first-page":"697","article-title":"[Small fiber neuropathy in systemic autoimmune diseases]","volume":"17","author":"Breville","year":"2021","journal-title":"Rev Med Suisse"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/2045-3701-2-24"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2015.01.010"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep361"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01986-8"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk7832"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.180239"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1097\/01.bor.0000245727.40630.c3"},{"issue":"4","key":"B60","first-page":"650","article-title":"Localized scleroderma severity index and global assessments: a pilot study of outcome instruments","volume":"35","author":"Arkachaisri","year":"2008","journal-title":"J Rheumatol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-020-02343-4"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1140\/epjb\/e2013-40829-0"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4314"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35319-w"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179182"},{"issue":"5","key":"B67","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1214\/15-AOS1337","article-title":"Controlling the false discovery rate via knockoffs","volume":"43","author":"Barber","year":"2015","journal-title":"Ann Stat"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/185758\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T20:20:30Z","timestamp":1779135630000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/185758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":67,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,2,27]]},"published-print":{"date-parts":[[2025,4,8]]}},"alternative-id":["10.1172\/jci.insight.185758"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.185758","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,8]]},"article-number":"e185758"}}