2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T660,Localized scleroderma (LoS) and systemic sclerosis (SSc) are both fibrotic diseases, but LoS is limited to the skin, whereas SSc involves systemic organ fibrosis. This study aimed to elucidate the mechanisms underlying these differences. Skin biopsies from 3 healthy controls, 3 patients with LoS, and 3 patients with SSc underwent immunofluorescence and single-cell RNA sequencing (scRNA-seq). Key molecular functions were validated using in vitro assays and murine models. Immunofluorescence revealed a high prevalence of tertiary lymphoid structures (TLS) in LoS lesions (65.7%) compared to SSc (14.3%, p = 0.0013). scRNA-seq identified T follicular helper (Tfh) cells enriched within TLS in LoS. Tfh cells likely promote B cell recruitment via the CXCL13/CXCR5 axis, and integrin α4 may support Tfh cell retention, contributing to TLS stability. These organized immune aggregates, together with elevated TGF-β expression, may drive localized fibroblast activation and skin fibrosis in LoS. In contrast, SSc lesions contained fibroblasts with high CREB3L1 expression. CREB3L1 overexpression increased type I collagen, fibronectin 1, and periostin levels in fibroblasts, while knockdown reduced them. In a SSc mouse model, CREB3L1 upregulation worsened skin and lung fibrosis, whereas knockdown alleviated it. These findings suggest that LoS fibrosis is driven by TLS-mediated local immune activation, whereas the systemic activation of CREB3L1-expressing fibroblasts plays an important role in SSc fibrosis. Targeting local inflammation may benefits LoS, while targeting CREB3L1 offers a promising antifibrotic strategy in SSc.31:T9b5, Objectives Localized scleroderma (LoS) and systemic sclerosis (SSc) are both fibrotic diseases, but LoS is limited to the skin, whereas SSc involves systemic organ fibrosis. This study aimed to elucidate the mechanisms underlying these differences. Methods Skin biopsies from 3 healthy controls, 3 patients with LoS, and 3 patients with SSc underwent immunofluorescence and single‐cell RNA sequencing (scRNA‐seq). Key molecular functions were validated using in vitro assays and murine models. Results Immunofluorescence revealed a high prevalence of tertiary lymphoid structures (TLS) in LoS lesions (65.7%) compared to SSc (14.3%, p = 0.0013). scRNA‐seq identified T follicular helper (Tfh) cells enriched within TLS in LoS. Tfh cells likely promote B cell recruitment via the CXCL13/CXCR5 axis, and integrin α4 may support Tfh cell retention, contributing to TLS stability. These organized immune aggregates, together with elevated TGF‐β expression, may drive localized fibroblast activation and skin fibrosis in LoS. In contrast, SSc lesions contained fibroblasts with high CREB3L1 expression. CREB3L1 overexpression increased type I collagen, fibronectin 1, and periostin levels in fibroblasts, while knockdown reduced them. In a SSc mouse model, CREB3L1 upregulation worsened skin and lung fibrosis, whereas knockdown alleviated it. Conclusion These findings suggest that LoS fibrosis is driven by TLS‐mediated local immune activation, whereas the systemic activation of CREB3L1‐expressing fibroblasts plays an important role in SSc fibrosis. Targeting local inflammation may benefits LoS, while targeting CREB3L1 offers a promising antifibrotic strategy in SSc. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Localized Scleroderma: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Localized Scleroderma (condition). Clinician-written summaries and actionable practice insights. Updated daily.\",\"url\":\"https://www.reachrx.ai/hub/tag/condition/Localized%20Scleroderma\",\"breadcrumb\":{\"@type\":\"BreadcrumbList\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https://www.reachrx.ai\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Research Hub\",\"item\":\"https://www.reachrx.ai/hub\"},{\"@type\":\"ListItem\",\"position\":3,\"name\":\"Conditions\",\"item\":\"https://www.reachrx.ai/hub/tag/condition\"},{\"@type\":\"ListItem\",\"position\":4,\"name\":\"Localized Scleroderma\",\"item\":\"https://www.reachrx.ai/hub/tag/condition/Localized%20Scleroderma\"}]}}"}}]],["$","$L2f",null,{"title":"Localized Scleroderma: Research & Clinical Takeaways","description":"Discover peer-reviewed research on Localized Scleroderma with concise clinician summaries and next-step guidance.","papers":[{"doi":"10.1002/art.70039","pmid":"41451447","title":"Single‐Cell Profiling Reveals Divergent Mechanisms of Fibrosis in Localized Scleroderma and Systemic Sclerosis","journal_title":"Arthritis & Rheumatology","journal_issn":"2326-5191","published_at":"2025-12-26T00:00:00.000Z","url":"https://doi.org/10.1002/art.70039","source_score":12,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2025-12-31","doi":"10.1002/art.70039","days":"30","issn":"2326-5191","rank":"8","field":"Clinical Medicine","score":"12","category":"Rheumatology","categories":["Rheumatology"],"_categories":["Rheumatology"]},"pubmed":{"doi":"10.1002/art.70039","title":"Single-Cell Profiling Reveals Divergent Mechanisms of Fibrosis in Localized Scleroderma and Systemic Sclerosis.","journal":"Arthritis & rheumatology (Hoboken, N.J.)","methods":"","results":"Immunofluorescence revealed a high prevalence of tertiary lymphoid structures (TLS) in LoS lesions (65.7%) compared to SSc (14.3%, p = 0.0013). scRNA-seq identified T follicular helper (Tfh) cells enriched within TLS in LoS. Tfh cells likely promote B cell recruitment via the CXCL13/CXCR5 axis, and integrin α4 may support Tfh cell retention, contributing to TLS stability. These organized immune aggregates, together with elevated TGF-β expression, may drive localized fibroblast activation and skin fibrosis in LoS. In contrast, SSc lesions contained fibroblasts with high CREB3L1 expression. CREB3L1 overexpression increased type I collagen, fibronectin 1, and periostin levels in fibroblasts, while knockdown reduced them. In a SSc mouse model, CREB3L1 upregulation worsened skin and lung fibrosis, whereas knockdown alleviated it.","abstract":"$30","keywords":[],"pubmed_id":"41451447","conclusions":"These findings suggest that LoS fibrosis is driven by TLS-mediated local immune activation, whereas the systemic activation of CREB3L1-expressing fibroblasts plays an important role in SSc fibrosis. Targeting local inflammation may benefits LoS, while targeting CREB3L1 offers a promising antifibrotic strategy in SSc.","publication_date":"2025-12-26T00:00:00"},"crossref":{"DOI":"10.1002/art.70039","URL":"https://doi.org/10.1002/art.70039","ISSN":["2326-5191","2326-5205"],"link":[{"URL":"https://acrjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/art.70039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Single‐Cell Profiling Reveals Divergent Mechanisms of Fibrosis in Localized Scleroderma and Systemic Sclerosis"],"author":[{"given":"Junxia","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Xue","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Xiuyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Liuting","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Manna","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Linzhu","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Yuqing","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Feifei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]},{"given":"Xinzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Minhang Meilong Branch, Zhongshan Hospital Fudan University Shanghai China"}]},{"given":"Xue","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Huashan Hospital Fudan University Shanghai China"},{"name":"Institute of Rheumatology, Immunology and Allergy Fudan University Shanghai China"}]},{"given":"Ji","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhongshan Hospital of Fudan University Shanghai 200032 China"}]}],"issued":{"date-parts":[[2025,12,26]]},"member":"311","prefix":"10.1002","source":"Crossref","volume":null,"archive":["Portico"],"created":{"date-time":"2025-12-26T09:40:52Z","timestamp":1766742052000,"date-parts":[[2025,12,26]]},"indexed":{"date-time":"2025-12-26T09:46:27Z","timestamp":1766742387633,"date-parts":[[2025,12,26]]},"license":[{"URL":"http://onlinelibrary.wiley.com/termsAndConditions#vor","start":{"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000,"date-parts":[[2025,12,26]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":"$31","language":"en","relation":{},"resource":{"primary":{"URL":"https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.70039"}},"subtitle":[],"assertion":[{"name":"received","group":{"name":"publication_history","label":"Publication History"},"label":"Received","order":0,"value":"2025-07-20"},{"name":"accepted","group":{"name":"publication_history","label":"Publication 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Sclerosis","value_numeric":null},{"paper_doi":"10.1002/art.70039","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1002/art.70039","tag_type":"sample_size","value":"n=9","value_numeric":9},{"paper_doi":"10.1002/art.70039","tag_type":"study_design","value":"Cross-Sectional","value_numeric":null},{"paper_doi":"10.1002/art.70039","tag_type":"warning","value":"Design spans human cross‑sectional tissue profiling plus in vitro and murine models; classification is approximate.","value_numeric":null},{"paper_doi":"10.1002/art.70039","tag_type":"warning","value":"TLS prevalence percentages appear lesion‑based; denominators and counting methods are not provided.","value_numeric":null}],"summaries":{"what_studied":"Skin from 3 healthy controls, 3 localized scleroderma (LoS), and 3 systemic sclerosis (SSc) patients was profiled by immunofluorescence and single‑cell RNA‑seq, with key pathways tested in vitro and in a SSc mouse model.","key_result":"LoS lesions showed more tertiary lymphoid structures than SSc (65.7% vs 14.3%; p=0.0013), with T follicular helper cells enriched and linked to B‑cell recruitment (CXCL13/CXCR5) and retention (integrin α4). SSc lesions had fibroblasts with high CREB3L1; its overexpression increased type I collagen, fibronectin 1, and periostin, while knockdown reduced them; in a SSc mouse model, CREB3L1 upregulation worsened skin and lung fibrosis and knockdown alleviated it.","limitations":"Very small human sample (3 per disease group and 3 controls); TLS rates are lesion‑level percentages with unspecified denominators; mechanistic inferences rely on in vitro and murine models without clinical outcomes.","practice_takeaway":"In LoS, findings support targeting local TLS‑driven immune activation; in SSc, CREB3L1 emerges as a plausible antifibrotic target. These mechanistic signals need clinical validation before changing practice."}}],"initialOffset":1,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Localized Scleroderma"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Localized Scleroderma"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Localized Scleroderma"}}}]]

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