{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:16:22Z","timestamp":1789895782164,"version":"4.0.1"},"reference-count":62,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rosetrees Trust","award":["M429-FI"],"award-info":[{"award-number":["M429-FI"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Systemic sclerosis (SSc) is an autoimmune fibrotic disorder affecting the skin and internal organs, categorized as either limited cutaneous SSc, where distal areas of skin are involved, or diffuse cutaneous SSc, where more extensive proximal skin involvement is seen. Vascular remodelling and internal organ involvement are frequent complications in both subsets. Multiple pathogenic mechanisms have been demonstrated, including production of disease-specific autoantibodies, endothelial cell damage at an early stage, infiltration of involved tissues by immune cells, as well as environmental factors triggering the onset such as solvents and viruses. Although not strongly familial, susceptibility to SSc is associated with multiple single nucleotide polymorphisms in immunoregulatory genes relevant to antigen presentation, T cell signalling and adaptive immunity, as well as innate immunity. In addition, several lines of evidence demonstrate abnormalities within the epithelial cell layer in SSc. Macroscopically, the SSc epidermis is pigmented, thickened and stiff and strongly promotes myofibroblasts in co-culture. Moreover, multiple activating factors and pathways have been implicated in the disease epidermis, including wound healing responses, induction of damage associated molecular patterns (DAMPS) and the release of pro-fibrotic growth factors and cytokines. Similar to SSc, data from studies of cutaneous wound healing indicate a major role for epidermal keratinocytes in regulating local fibroblast responses during repair of the wound defect. Since the epithelium is strongly exposed to environmental factors and richly populated with protective immune cells, it is possible that disease-initiating mechanisms in SSc involve dysregulated immunity and tissue repair within this cell layer. Treatments designed to restore epithelial homeostasis or else disrupt epithelial\u2013fibroblast cross-talk could be of benefit in this severe and resistant disease. Accordingly, single cell analysis has confirmed an active signature in SSc keratinocytes, which was partially reversed following a period of JAK inhibitor therapy.<\/jats:p>","DOI":"10.3390\/cells14130962","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:44:41Z","timestamp":1750761881000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Understanding the Role of Epithelial Cells in the Pathogenesis of Systemic Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Lydia","family":"Nagib","sequence":"first","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London NW32PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshul Sheel","family":"Kumar","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London NW32PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2948-6919","authenticated-orcid":false,"given":"Richard","family":"Stratton","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London NW32PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"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":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. 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