{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:00:54Z","timestamp":1791021654052,"version":"4.1.0"},"reference-count":188,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-KPQ-109-BioMed"],"award-info":[{"award-number":["AS-KPQ-109-BioMed"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["110-M5030"],"award-info":[{"award-number":["110-M5030"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative\/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-\u03b1, and TNF-\u03b1, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11\/U12 RNP), anti-nucleolar antigens (anti-Th\/T0, anti-NOR90, anti-Ku, anti-RuvBL1\/2, and anti-PM\/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.<\/jats:p>","DOI":"10.3390\/cells10123402","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T21:19:08Z","timestamp":1638479948000},"page":"3402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3218-0689","authenticated-orcid":false,"given":"Chieh-Yu","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-9438","authenticated-orcid":false,"given":"Cheng-Hsun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Han","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko-Jen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Min","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Chou","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4988-0400","authenticated-orcid":false,"given":"Chia-Li","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/exd.12673","article-title":"Current frontiers in systemic sclerosis pathogenesis","volume":"24","author":"Ciechomska","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1007\/s12026-017-8926-y","article-title":"Pathogenesis of systemic sclerosis-current concept and emerging treatments","volume":"65","author":"Furue","year":"2017","journal-title":"Immunol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/cge.12946","article-title":"Systematic approach to understanding the pathogenesis of systemic sclerosis","volume":"92","author":"Zuo","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_5","first-page":"3","article-title":"One year in review 2020: Systemic sclerosis","volume":"38","author":"Orlandi","year":"2020","journal-title":"Clin. Exp. Rheumatol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1684\/ejd.2008.0570","article-title":"Scleroderma--pathophysiology","volume":"19","author":"Yamamoto","year":"2009","journal-title":"Eur. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1056\/NEJMra0806188","article-title":"Scleroderma","volume":"360","author":"Gabrielli","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.imlet.2018.01.002","article-title":"Pathogenic roles of B lymphocytes in systemic sclerosis","volume":"195","author":"Yoshizaki","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1172\/JCI31139","article-title":"Systemic sclerosis: A prototypic multisystem fibrotic disorder","volume":"117","author":"Varga","year":"2007","journal-title":"J. Clin. Invest."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tsai, C.Y., Hsieh, S.C., Wu, T.H., Li, K.J., Shen, C.Y., Liao, H.T., Wu, C.H., Kuo, Y.M., Lu, C.S., and Yu, C.L. (2020). Pathogenic Roles of Autoantibodies and Aberrant Epigenetic Regulation of Immune and Connective Tissue Cells in the Tissue Fibrosis of Patients with Systemic Sclerosis. Int. J. Mol. Sci, 21.","DOI":"10.3390\/ijms21093069"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.2741\/1654","article-title":"Immunology of systemic sclerosis","volume":"10","author":"Artlett","year":"2005","journal-title":"Front. Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11926-014-0473-0","article-title":"Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis","volume":"17","author":"Jimenez","year":"2015","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1111\/jcmm.13630","article-title":"Oxidative stress in the pathogenesis of systemic scleroderma: An overview","volume":"22","author":"Vona","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.3389\/fphys.2018.01177","article-title":"The Role of Oxidative Stress in the Development of Systemic Sclerosis Related Vasculopathy","volume":"9","author":"Abdulle","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1080\/10715762.2018.1525712","article-title":"Oxidative\/nitrative stress in the pathogenesis of systemic sclerosis: Are antioxidants beneficial?","volume":"52","author":"Ames","year":"2018","journal-title":"Free Radic. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.freeradbiomed.2018.04.554","article-title":"NADPH oxidase, oxidative stress and fibrosis in systemic sclerosis","volume":"125","author":"Svegliati","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/cei.13426","article-title":"Toll-like receptors in mediating pathogenesis in systemic sclerosis","volume":"201","author":"Frasca","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Giovannetti, A., Straface, E., Rosato, E., Casciaro, M., Pioggia, G., and Gangemi, S. (2020). Role of Alarmins in the Pathogenesis of Systemic Sclerosis. Int. J. Mol. Sci.","DOI":"10.3390\/ijms21144985"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s10067-008-0958-1","article-title":"The impact of systemic sclerosis on arterial wall stiffness parameters and endothelial function","volume":"27","author":"Cypiene","year":"2008","journal-title":"Clin. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.2169\/internalmedicine.5226-20","article-title":"Premature Onset Aortic Stenosis in Systemic Sclerosis: A Report of a Series of Cases","volume":"59","author":"Machida","year":"2020","journal-title":"Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12016-018-8718-8","article-title":"Antinuclear Antibodies in Systemic Sclerosis: An Update","volume":"58","author":"Stochmal","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000251109","article-title":"Chromosomal breakage in systemic sclerosis and related disorders","volume":"153","author":"Emerit","year":"1976","journal-title":"Dermatologica"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1586\/1744666X.2013.850031","article-title":"Accelerated telomere shortening in rheumatic diseases: Cause or consequence?","volume":"9","author":"Dehbi","year":"2013","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/art.37969","article-title":"Cancer incidence in systemic sclerosis: Meta-analysis of population-based cohort studies","volume":"65","author":"Onishi","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.3389\/fimmu.2018.03112","article-title":"Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors","volume":"9","author":"Maria","year":"2018","journal-title":"Front. Immunol"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1080\/1744666X.2021.1847641","article-title":"Cancer risk in systemic sclerosis: Identifying risk and managing high-risk patients","volume":"16","author":"Fragoulis","year":"2020","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_27","first-page":"645","article-title":"Scleroderma, an ageing process? I. Clinical and immunological aspects (author\u2019s transl)","volume":"7","author":"Sandhofer","year":"1977","journal-title":"Aktuelle Gerontol"},{"key":"ref_28","first-page":"760","article-title":"Werner\u2019s syndrome: From clinics to genetics","volume":"18","author":"Goto","year":"2000","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1586\/1744666X.2016.1125782","article-title":"An overview of environmental risk factors in systemic sclerosis","volume":"12","author":"Ciccarelli","year":"2016","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00420-009-0505-7","article-title":"Occupational silica exposure as a risk factor for scleroderma: A meta-analysis","volume":"83","author":"McCormic","year":"2010","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41584-018-0099-0","article-title":"New insights into the genetics and epigenetics of systemic sclerosis","volume":"14","author":"Angiolilli","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1002\/art.11173","article-title":"Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies","volume":"48","author":"Medsger","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_33","first-page":"899","article-title":"Occurrence of rheumatoid arthritis in a nationwide series of twins","volume":"13","author":"Aho","year":"1986","journal-title":"J. Rheumatol."},{"key":"ref_34","first-page":"261","article-title":"Examinations of twins in multiple sclerosis","volume":"181","author":"Bammer","year":"1960","journal-title":"Dtsch. Z. Nervenheilkd"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1615\/CritRevImmunol.2020033247","article-title":"Clinical and Immunogenetic Aspects of Systemic Lupus Erythematosus","volume":"39","author":"Bhaskar","year":"2019","journal-title":"Crit. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1053\/j.gastro.2004.05.005","article-title":"Primary biliary cirrhosis in monozygotic and dizygotic twins: Genetics, epigenetics, and environment","volume":"127","author":"Selmi","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1146\/annurev-pathol-011110-130312","article-title":"The pathogenesis of systemic sclerosis","volume":"6","author":"Katsumoto","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1073\/pnas.1906593116","article-title":"HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry","volume":"117","author":"Gourh","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.humimm.2016.10.017","article-title":"Genomic and genetic studies of systemic sclerosis: A systematic review","volume":"78","author":"Chairta","year":"2017","journal-title":"Hum. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ajhg.2013.12.002","article-title":"Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis","volume":"94","author":"Mayes","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, J., Guo, X., Yi, L., Guo, G., Tu, W., Wu, W., Yang, L., Xiao, R., Li, Y., and Chu, H. (2014). Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087363"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1093\/rheumatology\/keu381","article-title":"Role of class II human leucocyte antigens in the progression from early to definite systemic sclerosis","volume":"54","author":"Vigone","year":"2015","journal-title":"Rheumatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1002\/1529-0131(200009)43:9<2005::AID-ANR11>3.0.CO;2-#","article-title":"HLA-DQA1*0501 is associated with diffuse systemic sclerosis in Caucasian men","volume":"43","author":"Lambert","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1002\/art.39765","article-title":"Brief Report: HLA-DRB1, DQA1, and DQB1 in Juvenile-Onset Systemic Sclerosis","volume":"68","author":"Stevens","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4955","DOI":"10.1038\/s41467-019-12760-y","article-title":"GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways","volume":"10","author":"Kerick","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2174\/1874312901408010029","article-title":"Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes","volume":"8","author":"Jin","year":"2014","journal-title":"Open Rheumatol. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s41232-021-00167-6","article-title":"Updates on genetics in systemic sclerosis","volume":"41","author":"Ota","year":"2021","journal-title":"Inflamm. Regen."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1136\/annrheumdis-2020-217116","article-title":"Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients","volume":"79","author":"Beretta","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s11596-019-2086-3","article-title":"Identification and Interaction Analysis of Key Genes and MicroRNAs in Systemic Sclerosis by Bioinformatics Approaches","volume":"39","author":"Sun","year":"2019","journal-title":"Curr. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1080\/08916934.2019.1621856","article-title":"MicroRNA-21 and microRNA-29a modulate the expression of collagen in dermal fibroblasts of patients with systemic sclerosis","volume":"52","author":"Gharibdoost","year":"2019","journal-title":"Autoimmunity"},{"key":"ref_51","first-page":"209","article-title":"Scleroderma in goldminers on the Witwatersrand with particular reference to pulmonary manifestations","volume":"3","author":"Erasmus","year":"1957","journal-title":"S. Afr. J. Lab. Clin. Med."},{"key":"ref_52","first-page":"838","article-title":"Silica, silicosis, and progressive systemic sclerosis","volume":"42","author":"Hessel","year":"1985","journal-title":"Br. J. Ind. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1136\/bmj.1.6015.936","article-title":"Immunological mechanisms in the pathogenesis of vinyl chloride disease","volume":"1","author":"Ward","year":"1976","journal-title":"Br. Med. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S0140-6736(65)90778-6","article-title":"Solvents and Scleroderma","volume":"2","author":"Walder","year":"1965","journal-title":"Lancet"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1159\/000250328","article-title":"Occupational scleroderma-like disorder occurring in men engaged in the polymerization of epoxy resins","volume":"161","author":"Yamakage","year":"1980","journal-title":"Dermatologica"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1093\/oxfordjournals.aje.a114608","article-title":"The association of oil ingestion with toxic oil syndrome in two convents","volume":"125","author":"Kilbourne","year":"1987","journal-title":"Am. J. Epidemiol."},{"key":"ref_57","first-page":"651","article-title":"Bleomycin-induced scleroderma","volume":"7","author":"Finch","year":"1980","journal-title":"J. Rheumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.autrev.2018.11.001","article-title":"Systemic sclerosis and exposure to heavy metals","volume":"18","author":"Marie","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1445-5994.2011.02706.x","article-title":"Stochastic processes in the aetiopathogenesis of scleroderma","volume":"42","author":"Walker","year":"2012","journal-title":"Intern. Med. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2013.01.010","article-title":"The critical importance of epigenetics in autoimmunity","volume":"41","author":"Lu","year":"2013","journal-title":"J. Autoimmun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.bbrc.2009.04.023","article-title":"CpG island methylation pattern in different human tissues and its correlation with gene expression","volume":"383","author":"Fan","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-3-319-43624-1_4","article-title":"Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases","volume":"945","author":"Tajima","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrg.2017.33","article-title":"TET-mediated active DNA demethylation: Mechanism, function and beyond","volume":"18","author":"Wu","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/cr.2011.42","article-title":"Readers of histone modifications","volume":"21","author":"Yun","year":"2011","journal-title":"Cell Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1756-8935-7-36","article-title":"Predicting expression: The complementary power of histone modification and transcription factor binding data","volume":"7","author":"Budden","year":"2014","journal-title":"Epigenetics Chromatin"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1080\/03009740902758875","article-title":"Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis","volume":"38","author":"Lei","year":"2009","journal-title":"Scand. J. Rheumatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/bjd.12913","article-title":"DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis","volume":"171","author":"Wang","year":"2014","journal-title":"Br. J. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000450949","article-title":"Disease Manifestation and Inflammatory Activity as Modulators of Th17\/Treg Balance and RORC\/FoxP3 Methylation in Systemic Sclerosis","volume":"171","author":"Almanzar","year":"2016","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"108756","DOI":"10.1016\/j.clim.2021.108756","article-title":"DNA methylation patterns in juvenile systemic sclerosis and localized scleroderma","volume":"228","author":"Coit","year":"2021","journal-title":"Clin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Baker Frost, D., da Silveira, W., Hazard, E.S., Atanelishvili, I., Wilson, R.C., Flume, J., Day, K.L., Oates, J.C., Bogatkevich, G.S., and Feghali-Bostwick, C. (2021). Differential DNA Methylation Landscape in Skin Fibroblasts from African Americans with Systemic Sclerosis. Genes, 12.","DOI":"10.3390\/genes12020129"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1111\/1756-185X.13175","article-title":"IRF7 gene expression profile and methylation of its promoter region in patients with systemic sclerosis","volume":"20","author":"Rezaei","year":"2017","journal-title":"Int. J. Rheum Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.jid.2017.12.003","article-title":"Genome-Wide DNA Methylation Analysis in Systemic Sclerosis Reveals Hypomethylation of IFN-Associated Genes in CD4(+) and CD8(+) T Cells","volume":"138","author":"Ding","year":"2018","journal-title":"J. Invest. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3389\/fgene.2019.00223","article-title":"Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.clim.2013.06.006","article-title":"Aberrant histone modification in peripheral blood B cells from patients with systemic sclerosis","volume":"149","author":"Wang","year":"2013","journal-title":"Clin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1136\/annrheumdis-2012-201615","article-title":"Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis","volume":"72","author":"Kramer","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1002\/art.39602","article-title":"Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2","volume":"68","author":"Ciechomska","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1136\/annrheumdis-2018-214295","article-title":"Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting","volume":"78","author":"Castellucci","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.biocel.2015.05.023","article-title":"Epigenetic mechanisms: An emerging role in pathogenesis and its therapeutic potential in systemic sclerosis","volume":"67","author":"Luo","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.humimm.2018.01.003","article-title":"Epigenetics and pathogenesis of systemic sclerosis; the ins and outs","volume":"79","author":"Aslani","year":"2018","journal-title":"Hum. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/sji.12595","article-title":"Epigenetics: The Future Direction in Systemic Sclerosis","volume":"86","author":"Walczyk","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"ref_82","first-page":"1675","article-title":"Immune system, cell senescence, aging and longevity--inflamm-aging reappraised","volume":"19","author":"Salvioli","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/S0264-410X(99)00513-7","article-title":"Human immunosenescence: The prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space","volume":"18","author":"Franceschi","year":"2000","journal-title":"Vaccine"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1152\/physiol.00040.2007","article-title":"Aging of the immune system as a prognostic factor for human longevity","volume":"23","author":"Larbi","year":"2008","journal-title":"Physiology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.mad.2016.12.008","article-title":"Inflammaging and human longevity in the omics era","volume":"165","author":"Monti","year":"2017","journal-title":"Mech. Ageing Dev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3389\/fimmu.2017.01960","article-title":"Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?","volume":"8","author":"Fulop","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/10253890500100240","article-title":"Stress, glucocorticoids and ageing of the immune system","volume":"8","author":"Bauer","year":"2005","journal-title":"Stress"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7","DOI":"10.14310\/horm.2002.1217","article-title":"Psychological and metabolic stress: A recipe for accelerated cellular aging?","volume":"8","author":"Epel","year":"2009","journal-title":"Hormones"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bbi.2014.05.016","article-title":"Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers","volume":"41","author":"Miller","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.psyneuen.2018.10.019","article-title":"Stress and immunosenescence: The role of telomerase","volume":"101","author":"Heim","year":"2019","journal-title":"Psychoneuroendocrinology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.arr.2013.05.001","article-title":"MicroRNAs linking inflamm-aging, cellular senescence and cancer","volume":"12","author":"Olivieri","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fmed.2015.00085","article-title":"Berindan-Neagoe, I. Inflamma-miRs in Aging and Breast Cancer: Are They Reliable Players?","volume":"2","author":"Catana","year":"2015","journal-title":"Front. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"111127","DOI":"10.1016\/j.mad.2019.111127","article-title":"Inflamm-aging microRNAs may integrate signals from food and gut microbiota by modulating common signalling pathways","volume":"182","author":"Teodori","year":"2019","journal-title":"Mech. Ageing Dev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.18632\/aging.101452","article-title":"Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype","volume":"10","author":"Lammermann","year":"2018","journal-title":"Aging"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mad.2017.02.008","article-title":"Exosome-based immunomodulation during aging: A nano-perspective on inflamm-aging","volume":"168","author":"Prattichizzo","year":"2017","journal-title":"Mech. Ageing Dev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.exger.2014.03.002","article-title":"MitomiRs in human inflamm-aging: A hypothesis involving miR-181a, miR-34a and miR-146a","volume":"56","author":"Rippo","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2309034","DOI":"10.1155\/2017\/2309034","article-title":"Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?","volume":"2017","author":"Giuliani","year":"2017","journal-title":"Mediators. Inflamm."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1101\/gad.290635.116","article-title":"The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration","volume":"31","author":"Ritschka","year":"2017","journal-title":"Genes Dev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cyto.2019.01.013","article-title":"The senescence-associated secretory phenotype and its regulation","volume":"117","author":"Rowell","year":"2019","journal-title":"Cytokine"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, cellular senescence, and cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Ragu, S., Matos-Rodrigues, G., and Lopez, B.S. (2020). Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response. Genes, 11.","DOI":"10.3390\/genes11040409"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.exger.2016.05.010","article-title":"Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype","volume":"82","author":"Malaquin","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_103","first-page":"837","article-title":"Spontaneous and clastogen induced chromosomal breakage in scleroderma","volume":"18","author":"Wolff","year":"1991","journal-title":"J. Rheumatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/BF00301010","article-title":"Chromosome abnormalities in peripheral lymphocytes from patients with progressive systemic sclerosis","volume":"12","author":"Takeuchi","year":"1993","journal-title":"Rheumatol. Int."},{"key":"ref_105","first-page":"153","article-title":"Genomic instability in scleroderma","volume":"22","author":"Male","year":"2004","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/rheumatology\/35.8.732","article-title":"Telomere reduction in scleroderma patients: A possible cause for chromosomal instability","volume":"35","author":"Artlett","year":"1996","journal-title":"Br. J. Rheumatol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1136\/ard.2007.086652","article-title":"Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion","volume":"67","author":"MacIntyre","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1136\/annrheumdis-2018-214499","article-title":"Short lymphocyte, but not granulocyte, telomere length in a subset of patients with systemic sclerosis","volume":"78","author":"Lakota","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_109","first-page":"223","article-title":"Biological age in patients with progressive scleroderma","volume":"29","author":"Sauer","year":"1996","journal-title":"Z. Gerontol. Geriatr."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1046\/j.1365-2133.2002.04937.x","article-title":"The polymorphism of telomerase RNA component gene in patients with systemic sclerosis","volume":"147","author":"Ohtsuka","year":"2002","journal-title":"Br. J. Dermatol"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/s00296-007-0472-9","article-title":"Telomerase activity in connective tissue diseases: Elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis","volume":"28","author":"Tarhan","year":"2008","journal-title":"Rheumatol. Int."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"458","DOI":"10.3899\/jrheum.130376","article-title":"Patients with systemic sclerosis present increased DNA damage differentially associated with DNA repair gene polymorphisms","volume":"41","author":"Palomino","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"582401","DOI":"10.3389\/fimmu.2020.582401","article-title":"Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis","volume":"11","author":"Vlachogiannis","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00508-014-0534-4","article-title":"Evaluation of oxidant and antioxidant status and relation with prolidase in systemic sclerosis","volume":"126","author":"Savas","year":"2014","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1046\/j.1523-1747.1999.00476.x","article-title":"Monocytes of patients wiht systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion","volume":"112","author":"Sambo","year":"1999","journal-title":"J. Invest. Dermatol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.amjmed.2003.11.022","article-title":"Acute and sustained effects of dihydropyridine-type calcium channel antagonists on oxidative stress in systemic sclerosis","volume":"116","author":"Allanore","year":"2004","journal-title":"Am. J. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/ard.2006.067504","article-title":"Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis","volume":"66","author":"Servettaz","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1002\/1529-0131(200111)44:11<2653::AID-ART445>3.0.CO;2-1","article-title":"Oxidative stress in scleroderma: Maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway","volume":"44","author":"Sambo","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s10067-011-1695-4","article-title":"Increasing levels of serum antioxidant status, total antioxidant power, in systemic sclerosis","volume":"30","author":"Ogawa","year":"2011","journal-title":"Clin. Rheumatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1002\/art.1780390711","article-title":"Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma","volume":"39","author":"Stein","year":"1996","journal-title":"Arthritis Rheum."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1093\/rheumatology\/kel012","article-title":"Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis","volume":"45","author":"Ogawa","year":"2006","journal-title":"Rheumatology"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.3899\/jrheum.080191","article-title":"Increased serum levels of N(epsilon)-(hexanoyl)lysine, a new marker of oxidative stress, in systemic sclerosis","volume":"35","author":"Shimizu","year":"2008","journal-title":"J. Rheumatol."},{"key":"ref_123","first-page":"659","article-title":"Serum levels of heat shock protein 70, a biomarker of cellular stress, are elevated in patients with systemic sclerosis: Association with fibrosis and vascular damage","volume":"26","author":"Ogawa","year":"2008","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13023-014-0123-7","article-title":"Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension","volume":"9","author":"Boin","year":"2014","journal-title":"Orphanet. J. Rare. Dis."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Giordo, R., Thuan, D.T.B., Posadino, A.M., Cossu, A., Zinellu, A., Erre, G.L., and Pintus, G. (2021). Iloprost Attenuates Oxidative Stress-Dependent Activation of Collagen Synthesis Induced by Sera from Scleroderma Patients in Human Pulmonary Microvascular Endothelial Cells. Molecules, 26.","DOI":"10.3390\/molecules26164729"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1002\/art.39242","article-title":"Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: Regulation by transforming growth factor beta","volume":"67","author":"Makul","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/art.39084","article-title":"A reactive oxygen species-mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis","volume":"67","author":"Spadoni","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13075-015-0591-8","article-title":"Intracellular free radical production by peripheral blood T lymphocytes from patients with systemic sclerosis: Role of NADPH oxidase and ERK1\/2","volume":"17","author":"Amico","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"101122","DOI":"10.1016\/j.redox.2019.101122","article-title":"Implication of oxidative stress in the pathogenesis of systemic sclerosis via inflammation, autoimmunity and fibrosis","volume":"25","author":"Doridot","year":"2019","journal-title":"Redox. Biol."},{"key":"ref_131","unstructured":"Mancini, O.K., Acevedo, M., Fazez, N., Cuillerier, A., Ruiz, A.F., Huynh, D.N., Burelle, Y., Ferbeyre, G., Baron, M., and Servant, M.J. (2021). Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients. Rheumatology, keab477."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11926-020-00920-9","article-title":"Mitochondria, Aging, and Cellular Senescence: Implications for Scleroderma","volume":"22","author":"Bueno","year":"2020","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.abd.2019.11.003","article-title":"Quantification of mitochondrial DNA damage and copy number in circulating blood of patients with systemic sclerosis by a qPCR-based assay","volume":"95","author":"Movassaghi","year":"2020","journal-title":"An. Bras. Dermatol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11926-018-0724-6","article-title":"Sirtuins and Accelerated Aging in Scleroderma","volume":"20","author":"Wyman","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/00062752-200105000-00001","article-title":"Aging and proinflammatory cytokines","volume":"8","author":"Bruunsgaard","year":"2001","journal-title":"Curr. Opin. Hematol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1007\/s00011-008-7243-2","article-title":"Exploring the complex relations between inflammation and aging (inflamm-aging): Anti-inflamm-aging remodelling of inflamm- aging, from robustness to frailty","volume":"57","author":"Giunta","year":"2008","journal-title":"Inflamm. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.jamda.2013.05.009","article-title":"Proinflammatory cytokines, aging, and age-related diseases","volume":"14","author":"Michaud","year":"2013","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1002\/eji.201343921","article-title":"Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for \u201cinflamm-aging\u201d","volume":"44","author":"Pinti","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.molimm.2015.01.015","article-title":"Circulating TNF and mitochondrial DNA are major determinants of neutrophil phenotype in the advanced-age, frail elderly","volume":"65","author":"Verschoor","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_140","first-page":"663","article-title":"Elevated serum tumor necrosis factor-alpha levels in patients with systemic sclerosis: Association with pulmonary fibrosis","volume":"24","author":"Hasegawa","year":"1997","journal-title":"J. Rheumatol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/j.1756-185X.2012.01755.x","article-title":"Serum leptin, resistin and TNF-alpha levels in patients with systemic sclerosis: The role of adipokines in scleroderma","volume":"15","author":"Pehlivan","year":"2012","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2217\/imt.13.173","article-title":"Potential use of TNF-alpha inhibitors in systemic sclerosis","volume":"6","author":"Murdaca","year":"2014","journal-title":"Immunotherapy"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/S0198-8859(99)00105-6","article-title":"TNF-alpha and TNF-beta gene polymorphisms in systemic sclerosis","volume":"60","author":"Pandey","year":"1999","journal-title":"Hum. Immunol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10238-019-00569-4","article-title":"TNFA -308G>A and -238G>A polymorphisms and risk to systemic sclerosis: Impact on TNF-alpha serum levels, TNFA mRNA expression, and autoantibodies","volume":"19","year":"2019","journal-title":"Clin. Exp. Med."},{"key":"ref_145","first-page":"328","article-title":"Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis","volume":"24","author":"Hasegawa","year":"1997","journal-title":"J. Rheumatol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"R147","DOI":"10.1186\/ar2821","article-title":"Plasma cytokine profiles in systemic sclerosis: Associations with autoantibody subsets and clinical manifestations","volume":"11","author":"Gourh","year":"2009","journal-title":"Arthritis. Res. Ther."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/ni1110-973","article-title":"IL-1 family nomenclature","volume":"11","author":"Dinarello","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.3389\/fimmu.2019.02025","article-title":"The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis","volume":"10","author":"Xu","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.3389\/fimmu.2018.01335","article-title":"Myocarditis: An Interleukin-1-Mediated Disease?","volume":"9","author":"Cavalli","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"653950","DOI":"10.3389\/fimmu.2021.653950","article-title":"Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement","volume":"12","author":"Cavalli","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_151","first-page":"308","article-title":"Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis","volume":"25","author":"Hasegawa","year":"1998","journal-title":"J. Rheumatol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.1346-8138.2010.00883.x","article-title":"Serum interleukin-6 level is reflected in elevated high-sensitivity C-reactive protein level in patients with systemic sclerosis","volume":"37","author":"Ohtsuka","year":"2010","journal-title":"J. Dermatol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1136\/annrheumdis-2018-213031","article-title":"Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: Insights from the faSScinate clinical trial in systemic sclerosis","volume":"77","author":"Denton","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1080\/14397595.2018.1559909","article-title":"The benefits and prospects of interleukin-6 inhibitor on systemic sclerosis","volume":"29","author":"Shima","year":"2019","journal-title":"Mod. Rheumatol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1111\/1756-185X.14194","article-title":"A bond between rheumatic diseases and cancer in the elderly: The interleukin-6 pathway","volume":"24","author":"Iorio","year":"2021","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1684\/ecn.2013.0325","article-title":"T cell abnormalities in systemic sclerosis with a focus on Th17 cells","volume":"23","author":"Brembilla","year":"2012","journal-title":"Eur. Cytokine. Netw."},{"key":"ref_157","first-page":"14","article-title":"Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis","volume":"34","author":"Lei","year":"2016","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"706","DOI":"10.5114\/aoms.2019.84738","article-title":"Serum concentrations of IL-17A, IL-17B, IL-17E and IL-17F in patients with systemic sclerosis","volume":"15","author":"Robak","year":"2019","journal-title":"Arch. Med. Sci."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s00296-019-04317-5","article-title":"Interleukin-17 pathways in systemic sclerosis-associated fibrosis","volume":"39","author":"Ahmed","year":"2019","journal-title":"Rheumatol. Int."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1186\/s13075-019-2074-9","article-title":"DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models","volume":"21","author":"Zhang","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/1756-185X.13769","article-title":"Effects of thalidomide on Th17, Treg cells and TGF-beta1\/Smad3 pathway in a mouse model of systemic sclerosis","volume":"23","author":"Lu","year":"2020","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"Franceschi","year":"2014","journal-title":"J. Gerontol. A. Biol. Sci. Med. Sci."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1007\/s10753-018-0949-6","article-title":"Aging and Hyperglycemia Intensify Dyslipidemia-Induced Oxidative Stress and Inflammation in Rats: Assessment of Restorative Potentials of ALA and EPA + DHA","volume":"42","author":"Acharya","year":"2019","journal-title":"Inflammation"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/prd.12135","article-title":"Aging, inflammation, immunity and periodontal disease","volume":"72","author":"Ebersole","year":"2016","journal-title":"Periodontol 2000"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"615486","DOI":"10.1155\/2015\/615486","article-title":"Mechanisms of Bone Resorption in Periodontitis","volume":"2015","author":"Hienz","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1111\/j.1834-7819.2009.01139.x","article-title":"The immunopathogenesis of periodontal disease","volume":"54","author":"Ohlrich","year":"2009","journal-title":"Aust. Dent. J."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/rheumatology\/kei244","article-title":"Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients","volume":"45","author":"Tan","year":"2006","journal-title":"Rheumatology"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1136\/annrheumdis-2019-215208","article-title":"Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis","volume":"78","author":"Wu","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"9919024","DOI":"10.1155\/2021\/9919024","article-title":"Inflamm-Aging-Related Cytokines of IL-17 and IFN-gamma Accelerate Osteoclastogenesis and Periodontal Destruction","volume":"2021","author":"Tan","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"587773","DOI":"10.3389\/fmed.2020.587773","article-title":"Classical Disease-Specific Autoantibodies in Systemic Sclerosis: Clinical Features, Gene Susceptibility, and Disease Stratification","volume":"7","author":"Yang","year":"2020","journal-title":"Front. Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s10067-017-3845-9","article-title":"Anti-CENP-B and anti-TOPO-1-containing sera from systemic sclerosis-related diseases with Raynaud\u2019s phenomenon induce vascular endothelial cell senescence not via classical p53-p21 pathway","volume":"37","author":"Shen","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1186\/s13075-020-02360-3","article-title":"Scleroderma-specific autoantibodies embedded in immune complexes mediate endothelial damage: An early event in the pathogenesis of systemic sclerosis","volume":"22","author":"Raschi","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_173","first-page":"1009","article-title":"Significance of anti-tubulin-alpha-1C autoantibody in systemic sclerosis","volume":"52","author":"Zhao","year":"2020","journal-title":"Beijing Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1136\/annrheumdis-2020-218918","article-title":"Autoantibodies targeting telomere-associated proteins in systemic sclerosis","volume":"80","author":"Adler","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1172\/JCI0215078","article-title":"CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse","volume":"109","author":"Saito","year":"2002","journal-title":"J. Clin. Invest."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1002\/art.20274","article-title":"Altered blood B lymphocyte homeostasis in systemic sclerosis: Expanded naive B cells and diminished but activated memory B cells","volume":"50","author":"Sato","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1002\/art.20674","article-title":"Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis","volume":"50","author":"Tsuchiya","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"686483","DOI":"10.3389\/fimmu.2021.686483","article-title":"Increased Frequency of Activated Switched Memory B Cells and Its Association With the Presence of Pulmonary Fibrosis in Diffuse Cutaneous Systemic Sclerosis Patients","volume":"12","author":"Simon","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.molimm.2004.06.025","article-title":"Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis","volume":"41","author":"Sato","year":"2004","journal-title":"Mol. Immunol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/BOR.0000000000000553","article-title":"T cells and cytokines in systemic sclerosis","volume":"30","author":"Fuschiotti","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1136\/ard.52.4.272","article-title":"Early phenotypic activation of circulating helper memory T cells in scleroderma: Correlation with disease activity","volume":"52","author":"Fiocco","year":"1993","journal-title":"Ann. Rheum. Dis."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/art.24432","article-title":"Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin-13 associated with increased skin fibrosis","volume":"60","author":"Fuschiotti","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1002\/art.30489","article-title":"GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production","volume":"63","author":"Medsger","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.3389\/fimmu.2018.02356","article-title":"Regulatory T Cells in Systemic Sclerosis","volume":"9","author":"Frantz","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Gumkowska-Sroka, O., Jagoda, K., Owczarek, A., Helbig, G., Giemza-Stoklosa, J., and Kotyla, P.J. (2019). Cytometric Characterization of Main Immunocompetent Cells in Patients with Systemic Sclerosis: Relationship with Disease Activity and Type of Immunosuppressive Treatment. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050625"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13075-021-02459-1","article-title":"Correction to: Lymphocyte subset abnormalities in early diffuse cutaneous systemic sclerosis","volume":"23","author":"Fox","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s12967-021-02916-0","article-title":"Correction to: Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts","volume":"19","author":"Moon","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.3389\/fimmu.2020.01602","article-title":"Systemic Sclerosis Perturbs the Architecture of the Immunome","volume":"11","author":"Paleja","year":"2020","journal-title":"Front. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:39:00Z","timestamp":1760168340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":188,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123402"],"URL":"https:\/\/doi.org\/10.3390\/cells10123402","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}