{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T02:26:27Z","timestamp":1786760787038,"version":"build-2736575974"},"reference-count":171,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T00:00:00Z","timestamp":1587945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2314-B-075-051-MY3"],"award-info":[{"award-number":["MOST 107-2314-B-075-051-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V107D37-002-MY3"],"award-info":[{"award-number":["V107D37-002-MY3"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic\/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-\u03b2, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-\u03b2 receptors on MFB, the downstream Wnt\/\u03b2-catenin triggers canonical Smad 2\/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested.<\/jats:p>","DOI":"10.3390\/ijms21093069","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T05:05:32Z","timestamp":1588050332000},"page":"3069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pathogenic Roles of Autoantibodies and Aberrant Epigenetic Regulation of Immune and Connective Tissue Cells in the Tissue Fibrosis of Patients with Systemic Sclerosis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4154-4018","authenticated-orcid":false,"given":"Chang-Youh","family":"Tsai","sequence":"first","affiliation":[{"name":"Division of Allergy, Immunology &amp; Rheumatology, Taipei Veterans General Hospital &amp; National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Chou","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Hung","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Taipei Veterans General Hospital &amp; National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-4620","authenticated-orcid":false,"given":"Ko-Jen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3218-0689","authenticated-orcid":false,"given":"Chieh-Yu","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"},{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Tzung","family":"Liao","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology &amp; Rheumatology, Taipei Veterans General Hospital &amp; National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Han","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"},{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, 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 and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"},{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-9438","authenticated-orcid":false,"given":"Cheng-Shiun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"},{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, 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 and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1097\/00002281-200311000-00016","article-title":"Autoimmunity in scleroderma: The origin, pathogenic role, and clinical significance of autoantibodies","volume":"15","author":"Harris","year":"2003","journal-title":"Curr. 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