{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:48:36Z","timestamp":1789058916198,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Juvenile localized scleroderma (LS) is an autoimmune disease of the skin whose pathogenesis is not well understood due to the rarity of the disease. This study was undertaken to determine the skin transcriptome in skin biopsy tissue from children with juvenile LS compared to pediatric healthy controls, with identification of significant molecular targets using RNA sequencing (RNA\u2010Seq). In this study, differentially expressed genes (DEGs) were assessed for correlations with histopathologic and clinical features in children with juvenile LS, and were used to group the children into distinct genetic clusters based on immunophenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>RNA\u2010Seq was performed on sections of paraffin\u2010embedded skin tissue obtained from 28 children with juvenile LS and 10 pediatric healthy controls. RNA\u2010Seq was carried out using an Illumina HTS TruSeq RNA Access library prep kit, with data aligned using STAR and data analysis using a DESeq2 platform. A standardized histologic scoring system was used to score skin sections for the severity of inflammation and levels of collagen deposition. Histologic scoring was completed by 2 pathologists who were blinded with regard to the status of each sample. Spearman\u2019s rank correlation coefficients were used to assess significant correlations between DEG expression profiles and skin histologic findings in patients with juvenile LS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 589 significant DEGs in children with juvenile LS as compared to healthy controls. Hierarchical clustering was used to demonstrate 3 distinct juvenile LS immunophenotype clusters. The histologic scores of skin inflammation (based on numbers and categories of inflammatory cell infiltrates) were significantly correlated with the expression levels of HLA\u2013DPB1, HLA\u2013DQA2, HLA\u2013DRA, and STAT1 genes (r<jats:sub>s<\/jats:sub> &gt; 0.5, <jats:italic>P<\/jats:italic> &lt; 0.01). Collagen thickness correlated with the expression levels of collagen organization genes as well as with genes found to be correlated with the severity of inflammation, including genes for major histocompatibility complex (MHC) class I, MHC class II, and interferon\u2010\u03b3 signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Among children with juvenile LS, 3 distinct genetic signatures, or clusters, were identified. In one cluster, inflammation\u2010related pathways were up\u2010regulated, corresponding to the histologic skin inflammation score. In the second cluster, fibrosis\u2010related pathways were up\u2010regulated. In the third cluster, gene expression in the skin corresponded to the patterns seen in healthy controls. Up\u2010regulation of HLA class II genes was observed within the first cluster (characterized by predominant inflammation), a feature that has also been observed in the peripheral blood of patients with morphea and in the skin of patients with systemic sclerosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41758","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T09:21:54Z","timestamp":1618219314000},"page":"1921-1930","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Transcriptomic Evaluation of Juvenile Localized Scleroderma Skin With Histologic and Clinical Correlation"],"prefix":"10.1002","volume":"73","author":[{"given":"Christina","family":"Schutt","sequence":"first","affiliation":[{"name":"University of Pittsburgh Medical Center, Children\u2019s Hospital of Pittsburgh Pittsburgh, Pennsylvania, and University of Rochester MedicalCenter and Golisano Children\u2019s Hospital  Rochester New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Mirizio","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Salgado","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Reyes\u2010Mugica","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjun","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"University of Pittsburgh University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorelei","family":"Grunwaldt","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaila L.","family":"Schollaert","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1662-143X","authenticated-orcid":false,"given":"Kathryn S.","family":"Torok","sequence":"additional","affiliation":[{"name":"University of Pittsburgh University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"73","article-title":"The epidemiology of morphea (localized scleroderma) in Olmsted County 1960\u20131993","volume":"24","author":"Peterson LS","year":"1997","journal-title":"J Rheumatol"},{"key":"e_1_2_7_3_1","first-page":"171","article-title":"Localized scleroderma in adults and children: clinical and laboratory investigations on 239 cases","volume":"13","author":"Marzano AV","year":"2003","journal-title":"Eur J Dermatol"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.09.025"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.04.001"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.04.008"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4378"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38853"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.081284"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep361"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2013.02.007"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.110210"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.17312"},{"key":"e_1_2_7_14_1","unstructured":"Illumina.bcl2fastq and bcl2fastq2 conversion software: software downloads. 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