{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:30:45Z","timestamp":1791898245421,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Dermatology Foundation (CDF)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Localized scleroderma (LS) is an autoimmune, fibrotic skin disease that is thought to be triggered by environmental factors. Recent evidence from systemic autoimmune diseases proposed that the induction of immunosenescence may link environmental triggers with autoimmunity development. We aimed to explore the inflammatory signature in juvenile LS and investigate the presence of DNA instability and immunosenescence using publicly available transcriptomic data. High-throughput RNA sequencing data from 28 juvenile LS and 10 healthy controls were analyzed. Unsupervised clustering, pathway analyses, cell-type enrichment, fusion analyses, and immunosenescence gene set enrichment were performed. IFN and Type 1\/2\/3 pathways were upregulated in clinically active and histologically inflammatory LS. Type 2 inflammatory signature in both inflammatory and fibrotic LS was demonstrated by enriched genes, pathways, and deconvolution analyses (eosinophils). Features of genotoxic stress signals manifesting as DNA instability genes, pathways, and fusion events as well as mitochondrial dysfunction were demonstrated for the first time in LS. Features of immunosenescence (e.g., the upregulation of pathways involved in T cell exhaustion, inhibitory receptors, and cellular senescence and the enrichment of senescent genes) were also confirmed in (active and inflammatory) LS. Immunosenescence and inflammaging may underlie the complex and heterogeneous nature of immune responses seen in LS and should be further studied.<\/jats:p>","DOI":"10.3390\/ijms26031258","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T04:36:51Z","timestamp":1738557411000},"page":"1258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7491-9386","authenticated-orcid":false,"given":"Lauren","family":"Khoury","sequence":"first","affiliation":[{"name":"Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Prosty","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Ghazal","sequence":"additional","affiliation":[{"name":"Division Dermatology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofianne","family":"Gabrielli","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn S.","family":"Torok","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Osman","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7726-4459","authenticated-orcid":false,"given":"Elvis","family":"Martinez-Jaramillo","sequence":"additional","affiliation":[{"name":"Division Dermatology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2939-7956","authenticated-orcid":false,"given":"Philippe","family":"Lefran\u00e7ois","sequence":"additional","affiliation":[{"name":"Division Dermatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Netchiporouk","sequence":"additional","affiliation":[{"name":"Division Dermatology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/01.bor.0000245727.40630.c3","article-title":"Localized scleroderma","volume":"18","author":"Laxer","year":"2006","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/art.41758","article-title":"Transcriptomic Evaluation of Juvenile Localized Scleroderma Skin With Histologic and Clinical Correlation","volume":"73","author":"Schutt","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"De Luca, D.A., Bieber, K., Vorobyev, A., and Ludwig, R.J. (2023). Morphea: The 2023 update. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1106318"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/BOR.0000000000000898","article-title":"Role of cellular senescence in the pathogenesis of systemic sclerosis","volume":"34","author":"Tsou","year":"2022","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1007\/s00011-022-01649-0","article-title":"Immunosenescence of T cells: A key player in rheumatoid arthritis","volume":"71","author":"Gao","year":"2022","journal-title":"Inflamm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1136\/annrheumdis-2018-214697","article-title":"Consensus-based recommendations for the management of juvenile localised scleroderma","volume":"78","author":"Zulian","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/bioinformatics\/bts356","article-title":"RSeQC: Quality control of RNA-seq experiments","volume":"28","author":"Wang","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1093\/bioinformatics\/btab135","article-title":"RNA-SeQC 2: Efficient RNA-seq quality control and quantification for large cohorts","volume":"37","author":"Graubert","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Leon, K.E., Buj, R., Lesko, E., Dahl, E.S., Chen, C.-W., Tangudu, N.K., Imamura-Kawasawa, Y., Kossenkov, A.V., Hobbs, R.P., and Aird, K.M. (2021). DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A. J. Cell Biol., 220.","DOI":"10.1083\/jcb.202008101"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Grzanka, M., and Piekie\u0142ko-Witkowska, A. (2021). The Role of Gene in Health and Disease: Beyond Treacher Collins Syndrome. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052482"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mirizio, E., Liu, C., Yan, Q., Waltermire, J., Mandel, R., Schollaert, K.L., Konnikova, L., Wang, X., Chen, W., and Torok, K.S. (2021). Genetic Signatures From RNA Sequencing of Pediatric Localized Scleroderma Skin. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.669116"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1111\/1346-8138.14161","article-title":"Diagnostic criteria, severity classification and guidelines of localized scleroderma","volume":"45","author":"Asano","year":"2018","journal-title":"J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1467-9868.2010.00746.x","article-title":"Discovering the false discovery rate: False Discovery Rate","volume":"72","author":"Benjamini","year":"2010","journal-title":"J. R. Stat. Soc. Series B Stat. Methodol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_19","unstructured":"Kolde (Pheatmap: Pretty Heatmaps, 2019). Pheatmap: Pretty Heatmaps."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W305","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","author":"Chen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1083","DOI":"10.1093\/nar\/gkx1042","article-title":"Human Ageing Genomic Resources: New and updated databases","volume":"46","author":"Tacutu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Aran, D., Hu, Z., and Butte, A.J. (2017). xCell: Digitally portraying the tissue cellular heterogeneity landscape. Genome Biol., 18.","DOI":"10.1186\/s13059-017-1349-1"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wickham (2009). Ggplot2: Elegant Graphics for Data Analysis, Springer.","DOI":"10.1007\/978-0-387-98141-3"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Haas, B.J., Dobin, A., Stransky, N., Li, B., Yang, X., Tickle, T., Bankapur, A., Ganote, C., Doak, T.G., and Pochet, N. (2017). STAR-Fusion: Fast and Accurate Fusion Transcript Detection from RNA-Seq. bioRxiv.","DOI":"10.1101\/120295"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1101\/gr.257246.119","article-title":"Accurate and efficient detection of gene fusions from RNA sequencing data","volume":"31","author":"Uhrig","year":"2021","journal-title":"Genome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"PEwels","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1056\/NEJMoa2202318","article-title":"Variant and Response to Ruxolitinib in an Autoinflammatory Syndrome","volume":"388","author":"Baghdassarian","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1002\/art.38814","article-title":"Major histocompatibility complex class I and class II alleles may confer susceptibility to or protection against morphea: Findings from the Morphea in Adults and Children cohort","volume":"66","author":"Jacobe","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/bjd.15001","article-title":"The molecular pathogenesis of morphoea: From genetics to future treatment targets","volume":"177","author":"Saracino","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000330324","article-title":"Irradiation-Induced Morphea: X-Rays as Triggers of Autoimmunity","volume":"223","author":"Laetsch","year":"2011","journal-title":"Dermatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-3-030-92616-8_7","article-title":"The Immunogenetics of Morphea and Lichen Sclerosus","volume":"1367","author":"Beigi","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1159\/000502030","article-title":"Incidence of Morphea following Adjuvant Irradiation of the Breast in 2,268 Patients","volume":"15","author":"Partl","year":"2020","journal-title":"Breast Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/1346-8138.13174","article-title":"Paraneoplastic eosinophilic fasciitis with generalized morphea and vitiligo in a patient working with organic solvents","volume":"43","author":"Hanami","year":"2016","journal-title":"J. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"221","DOI":"10.4103\/ijdvl.IJDVL_248_17","article-title":"Atypical generalized morphea-like scleroderma occurring in a patient exposed to organic solvents and having chronic hepatitis C virus infection","volume":"84","author":"Aounallah","year":"2018","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1007\/s12016-021-08889-8","article-title":"Current concepts on the pathogenesis of systemic sclerosis","volume":"64","author":"Truchetet","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1001\/jamadermatol.2020.0034","article-title":"Changes in Disease Activity and Damage Over Time in Patients With Morphea","volume":"156","author":"Nymeyer","year":"2020","journal-title":"JAMA Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13024-023-00672-x","article-title":"Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders","volume":"18","author":"Huang","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/nm.4027","article-title":"Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease","volume":"22","author":"Lood","year":"2016","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102847","DOI":"10.1016\/j.jaut.2022.102847","article-title":"Genomic instability in early systemic sclerosis","volume":"131","author":"Gniadecki","year":"2022","journal-title":"J. Autoimmun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.3899\/jrheum.2022-0827","article-title":"Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response","volume":"50","author":"ALonde","year":"2023","journal-title":"J. Rheumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1177\/12034754231194009","article-title":"Immunosenescence, Inflammaging, and Dermatology: Insights and Opportunities","volume":"27","author":"Zhu","year":"2023","journal-title":"J. Cutan. Med. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/s41577-021-00646-4","article-title":"Immune ageing at single-cell resolution","volume":"22","author":"Mogilenko","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, Y., Dong, C., Han, Y., Gu, Z., and Sun, C. (2022). Immunosenescence, aging and successful aging. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.942796"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"128","DOI":"10.2478\/rir-2022-0021","article-title":"The ABC-associated Immunosenescence and Lifestyle Interventions in Autoimmune Disease","volume":"3","author":"Ruan","year":"2022","journal-title":"Rheumatol. Immunol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Joly-Chevrier, M., G\u00e9linas, A., Ghazal, S., Moussa, S., McCuaig, C.C., Piram, M., Mereniuk, A., Litvinov, I.V., Osman, M., and Pehr, K. (2023). Morphea, Eosinophilic Fasciitis and Cancer: A Scoping Review. Cancers, 15.","DOI":"10.3390\/cancers15184450"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2300752","DOI":"10.1183\/13993003.00752-2023","article-title":"Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis","volume":"63","author":"Wijsenbeek","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jdcr.2022.09.024","article-title":"Tocilizumab for refractory morphea in adults: A case series","volume":"30","author":"Lonowski","year":"2022","journal-title":"JAAD Case Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.jid.2019.12.019","article-title":"Jak Inhibition Prevents Bleomycin-Induced Fibrosis in Mice and Is Effective in Patients with Morphea","volume":"140","author":"Damsky","year":"2020","journal-title":"J. Invest. Dermatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1258\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:25:05Z","timestamp":1760027105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,31]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26031258"],"URL":"https:\/\/doi.org\/10.3390\/ijms26031258","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,31]]}}}