{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T14:55:10Z","timestamp":1793890510351,"version":"4.8.0"},"reference-count":132,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by immune dysregulation, microvascular damage, and multi-organ fibrosis. Recent breakthroughs in single-cell and spatial multi-omics technologies have profoundly revealed the high heterogeneity of the SSc immune microenvironment, including extensive aberrant activation of innate immunity (e.g., dendritic cells, macrophages, neutrophils) and adaptive immunity (T cells, B cells), and their interaction with fibroblasts and endothelial cells through an \u201cimmune-stromal-vascular\u201d network that collectively drives the fibrotic process. These findings have advanced disease subtyping based on molecular features (e.g., inflammatory, fibrotic) and the development of precision therapeutic strategies. Emerging therapies targeting the IL-6 receptor (tocilizumab), B cells (rituximab, belimumab, CAR-T), the JAK-STAT pathway (tofacitinib, baricitinib), and T-cell co-stimulation (abatacept) have shown potential to improve disease progression in clinical studies. However, heterogeneity in treatment response, difficulty in reversing fibrosis, and the lack of biomarkers remain current challenges. Future efforts require integrating multi-omics and artificial intelligence technologies to build dynamic predictive models, promoting multi-target combination and individualized therapies, ultimately aiming for early intervention and long-term remission in SSc.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1713221","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T06:43:04Z","timestamp":1772433784000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The immune landscape of systemic sclerosis: from pathogenic mechanisms to precision therapeutic breakthroughs"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengguo","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.05.016","article-title":"Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis","volume":"84","author":"Ueberall","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2023.09.288","article-title":"Fibroblast subpopulations in systemic sclerosis: functional implications of individual subpopulations and correlations with clinical features","volume":"144","author":"Zhu","year":"2024","journal-title":"J Invest Dermatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4384","DOI":"10.1038\/s41467-021-24607-6","article-title":"Myofibroblast transcriptome indicates SFRP2(hi) fibroblast progenitors in systemic sclerosis skin","volume":"12","author":"Tabib","year":"2021","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljae286","article-title":"Atypical chemokine receptor 1-positive endothelial cells mediate leucocyte infiltration and synergize with secreted frizzled-related protein 2\/asporin-positive fibroblasts to promote skin fibrosis in systemic sclerosis","volume":"191","author":"Huang","year":"2024","journal-title":"Brit J Dermatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtauto.2025.100323","article-title":"TGF-beta1 promotes collagen synthesis in systemic sclerosis via upregulating P4HA3","volume":"11","author":"Chen","year":"2025","journal-title":"J Transl Autoimmun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224184","article-title":"Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups","volume":"82","author":"Clark","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"ard-2024-226336","DOI":"10.1136\/ard-2024-226336","article-title":"Imaging mass cytometry-based characterisation of fibroblast subsets and their cellular niches in systemic sclerosis","author":"Rius","year":"2024","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.04.025","article-title":"Spatial multiomics decipher fibroblast-macrophage dynamics in systemic sclerosis","volume":"84","author":"Li","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.06.002","article-title":"Spatially informed phenotyping by cyclic-in-situ-hybridisation identifies novel fibroblast populations and their pathogenic niches in systemic sclerosis","volume":"84","author":"Li","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.imlet.2017.11.003","article-title":"Dendritic cells in systemic sclerosis: Advances from human and mice studies","volume":"195","author":"Affandi","year":"2018","journal-title":"Immunol Lett"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010653","article-title":"CXCL4-RNA complexes circulate in systemic sclerosis and amplify inflammatory\/pro-fibrotic responses by myeloid dendritic cells","volume":"24","author":"Pietraforte","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-017-1106-7","article-title":"Increased frequencies of circulating CXCL10-, CXCL8- and CCL4-producing monocytes and Siglec-3-expressing myeloid dendritic cells in systemic sclerosis patients","volume":"67","author":"Carvalheiro","year":"2018","journal-title":"Inflammation Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/biology12020285","article-title":"Molecular mechanisms behind the role of plasmacytoid dendritic cells in systemic sclerosis","volume":"12","author":"Silva","year":"2023","journal-title":"Biology-Basel"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-025-03500-3","article-title":"Distinct metabolic profiles of circulating plasmacytoid dendritic cells in systemic sclerosis patients stratified by clinical phenotypes","volume":"27","author":"Ferreira","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10030491","article-title":"Implication of miR-126 and miR-139-5p in Plasmacytoid Dendritic Cell Dysregulation in Systemic Sclerosis","volume":"10","author":"Chouri","year":"2021","journal-title":"J Clin Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98380","article-title":"pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis","volume":"3","author":"Kafaja","year":"2018","journal-title":"JCI Insight"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e16206","article-title":"M2 macrophage polarization in systemic sclerosis fibrosis: pathogenic mechanisms and therapeutic effects","volume":"9","author":"Hu","year":"2023","journal-title":"Heliyon"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213648","article-title":"Increase in circulating cells coexpressing M1 and M2 macrophage surface markers in patients with systemic sclerosis","volume":"77","author":"Soldano","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-018-0891-z","article-title":"A circulating cell population showing both M1 and M2 monocyte\/macrophage surface markers characterizes systemic sclerosis patients with lung involvement","volume":"19","author":"Trombetta","year":"2018","journal-title":"Resp Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e128","DOI":"10.1136\/annrheumdis-2018-214371","article-title":"Monocyte and macrophage phenotypes: a look beyond systemic sclerosis. Response to: \u2018M1\/M2 polarisation state of M-CSF blood-derived macrophages in systemic sclerosis\u2019 by Lescoat et\u00a0al","volume":"78","author":"Cutolo","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.5114\/ceji.2021.109756","article-title":"Expression of macrophage migration inhibitory factor and its receptor CD74 in systemic sclerosis","volume":"46","author":"Banos-Hernandez","year":"2021","journal-title":"Cent Eur J Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e1042","DOI":"10.1002\/cti2.1042","article-title":"Analysis of serum macrophage migration inhibitory factor and D-dopachrome tautomerase in systemic sclerosis","volume":"7","author":"Vincent","year":"2018","journal-title":"Clin Transl Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1136\/annrheumdis-2017-212454","article-title":"Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk","volume":"77","author":"Moreno-Moral","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"R128","DOI":"10.1186\/ar3066","article-title":"Characterization of monocyte\/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis","volume":"12","author":"Higashi-Kuwata","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s13075-024-03379-6","article-title":"Elevated neutrophil extracellular traps in systemic sclerosis-associated vasculopathy and suppression by a synthetic prostacyclin analog","volume":"26","author":"Kortam","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9072136","article-title":"Neutrophil extracellular traps generation relates with early stage and vascular complications in systemic sclerosis","volume":"9","author":"Didier","year":"2020","journal-title":"J Clin Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.03.088","article-title":"Neutrophil-derived exosome from systemic sclerosis inhibits the proliferation and migration of endothelial cells","volume":"526","author":"Li","year":"2020","journal-title":"Biochem Bioph Res Co"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3906\/sag-1601-87","article-title":"Association of neutrophil\/lymphocyte ratio with the degree ofinterstitial lung disease in systemic sclerosis","volume":"46","author":"Atilla","year":"2016","journal-title":"Turk J Med Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24880","article-title":"Blood neutrophil count and neutrophil-to-lymphocyte ratio for prediction of disease progression and mortality in two independent systemic sclerosis cohorts","volume":"75","author":"Wareing","year":"2023","journal-title":"Arthrit Care Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/all.15073","article-title":"Patients with systemic sclerosis show phenotypic and functional defects in neutrophils","volume":"77","author":"Impellizzieri","year":"2022","journal-title":"Allergy"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5178","DOI":"10.1038\/s41598-025-89238-z","article-title":"Natural killer cells are decreased in systemic sclerosis and have diagnostic value for pulmonary arterial hypertension incorporation","volume":"15","author":"Guo","year":"2025","journal-title":"Sci Rep-Uk"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01665","article-title":"Natural killer cells exhibit a peculiar phenotypic profile in systemic sclerosis and are potent inducers of endothelial microparticles release","volume":"9","author":"Benyamine","year":"2018","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1186\/s13075-019-1991-y","article-title":"Invariant natural killer T cells are functionally impaired in patients with systemic sclerosis","volume":"21","author":"Pecher","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B34","article-title":"Reduced circulating natural killer T cells and gamma\/delta T cells in patients with systemic sclerosis","volume":"32","author":"Riccieri","year":"2005","journal-title":"J Rheumatol"},{"key":"B35","article-title":"Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis","volume":"27","author":"Meloni","year":"2009","journal-title":"Clin Exp Rheumatol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.jdermsci.2004.03.001","article-title":"Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis","volume":"35","author":"Fujii","year":"2004","journal-title":"J Dermatol Sci"},{"key":"B37","article-title":"Th1 and Th2 chemokine serum levels in systemic sclerosis in the presence or absence of autoimmune thyroiditis","volume":"35","author":"Antonelli","year":"2008","journal-title":"J Rheumatol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"R166","DOI":"10.1186\/ar3486","article-title":"Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease","volume":"13","author":"Truchetet","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-023-01125-x","article-title":"Type 2 cytokines and scleroderma interstitial lung disease","volume":"23","author":"Pellicano","year":"2023","journal-title":"Clin Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-018-4071-8","article-title":"Higher levels of serum interleukin-35 are associated with the severity of pulmonary fibrosis and Th2 responses in patients with systemic sclerosis","volume":"38","author":"Tang","year":"2018","journal-title":"Rheumatol Int"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2024.156534","article-title":"Th17\/IL-17A axis is critical for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc): SSc patients with high levels of serum IL-17A exhibit reduced lung functions and increased prevalence of PAH","volume":"176","author":"Seki","year":"2024","journal-title":"Cytokine"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01366-0","article-title":"GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2\/Th17 cells","volume":"56","author":"Jeong","year":"2024","journal-title":"Exp Mol Med"},{"key":"B43","doi-asserted-by":"publisher","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":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2010.09633.x","article-title":"Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea","volume":"162","author":"Antiga","year":"2010","journal-title":"Brit J Dermatol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s12016-016-8563-6","article-title":"Regulatory T cells in systemic sclerosis: a comprehensive review","volume":"52","author":"Slobodin","year":"2017","journal-title":"Clin Rev Allerg Immu"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.900638","article-title":"The pathophysiological roles of regulatory T cells in the early phase of systemic sclerosis","volume":"13","author":"Kobayashi","year":"2022","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.12.1932","article-title":"Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis","volume":"135","author":"MacDonald","year":"2015","journal-title":"J Allergy Clin Immun"},{"key":"B48","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1586\/eci.11.28","article-title":"CD4+CD25+ regulatory T cells in systemic sclerosis and other rheumatic diseases","volume":"7","author":"Michels-van","year":"2011","journal-title":"Expert Rev Clin Immu"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/390563","article-title":"Assessment of T regulatory cells and expanded profiling of autoantibodies may offer novel biomarkers for the clinical management of systemic sclerosis and undifferentiated connective tissue disease","volume":"2013","author":"Cordiali-Fei","year":"2013","journal-title":"Clin Dev Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.12.002","article-title":"New insights into CD4(+) T cell abnormalities in systemic sclerosis","volume":"28","author":"Liu","year":"2016","journal-title":"Cytokine Growth F R"},{"key":"B51","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1515\/rjim-2017-0027","article-title":"IL-17 and Th17 cells in systemic sclerosis: a comprehensive review","volume":"55","author":"Balanescu","year":"2017","journal-title":"Rom J Intern Med"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/s41598-025-85895-2","article-title":"Inhibition of skin fibrosis via regulation of Th17\/Treg imbalance in systemic sclerosis","volume":"15","author":"Sekiguchi","year":"2025","journal-title":"Sci Rep-Uk"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2011.01.013","article-title":"Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis","volume":"139","author":"Fenoglio","year":"2011","journal-title":"Clin Immunol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"84","DOI":"10.5493\/wjem.v7.i3.84","article-title":"Treg\/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients","volume":"7","author":"Krasimirova","year":"2017","journal-title":"World J Exp Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.09.037","article-title":"Imbalance between T helper 17 and regulatory T cell subsets plays a significant role in the pathogenesis of systemic sclerosis","volume":"108","author":"Mo","year":"2018","journal-title":"BioMed Pharmacother"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2014.12.008","article-title":"The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis","volume":"76","author":"Zhou","year":"2015","journal-title":"Hum Immunol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"R4","DOI":"10.1186\/ar4430","article-title":"Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction","volume":"16","author":"Yang","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B58","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","author":"Lei","year":"2016","journal-title":"Clin Exp Rheumatol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"R151","DOI":"10.1186\/ar4334","article-title":"Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts","volume":"15","author":"Brembilla","year":"2013","journal-title":"Arthritis Res Ther"},{"key":"B60","doi-asserted-by":"publisher","first-page":"4223","DOI":"10.1186\/s13075-014-0512-2","article-title":"Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway","volume":"16","author":"Liu","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B61","article-title":"Th17 pathway genes polymorphisms in Algerian patients with systemic sclerosis","volume":"43","author":"Mellal","year":"2018","journal-title":"Acta Reumatol Port"},{"key":"B62","doi-asserted-by":"publisher","first-page":"e24489","DOI":"10.1002\/jcla.24489","article-title":"Th17 cell-derived miR-155-5p modulates interleukin-17 and suppressor of cytokines signaling 1 expression during the progression of systemic sclerosis","volume":"36","author":"Han","year":"2022","journal-title":"J Clin Lab Anal"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214382","article-title":"Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib","volume":"78","author":"Ricard","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B64","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s10238-023-01286-9","article-title":"The relationship between peripheral T follicular helper cells and disease severity in systemic sclerosis","volume":"24","author":"Sahinoglu","year":"2024","journal-title":"Clin Exp Med"},{"key":"B65","doi-asserted-by":"publisher","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":"B66","article-title":"Reduced non-switched memory B cell subsets cause imbalance in B cell repertoire in systemic sclerosis","author":"Simon","year":"2016","journal-title":"Clin Exp Rheumatol"},{"key":"B67","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1002\/art.39437","article-title":"Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis","volume":"68","author":"Mavropoulos","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/art.41927","article-title":"Defective early B cell tolerance checkpoints in patients with systemic sclerosis allow the production of self antigen-specific clones","volume":"74","author":"Glauzy","year":"2022","journal-title":"Arthritis Rheumatol"},{"key":"B69","article-title":"Increased expression levels of Fc\u03b3RIIB on na\u00efve and double-negative memory B cells in patients with systemic sclerosis","volume":"37","author":"Yagi-Numata","year":"2019","journal-title":"Clin Exp Rheumatol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1213-9","article-title":"TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients","volume":"19","author":"Aravena","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B71","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1002\/art.21526","article-title":"Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes","volume":"54","author":"Matsushita","year":"2006","journal-title":"Arthritis Rheum"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1373464","article-title":"Characteristics and impact of infiltration of B-cells from systemic sclerosis patients in a 3D healthy skin model","volume":"15","author":"Le Maitre","year":"2024","journal-title":"Front Immunol"},{"key":"B73","doi-asserted-by":"publisher","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":"B74","doi-asserted-by":"publisher","DOI":"10.3390\/jpm12091420","article-title":"The effect of SARS-coV-2 vaccination on B-cell phenotype in systemic sclerosis patients","volume":"12","author":"Pellicano","year":"2022","journal-title":"J Pers Med"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215066","article-title":"Acyltransferase skinny hedgehog regulates TGFbeta-dependent fibroblast activation in SSc","volume":"78","author":"Liang","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B76","doi-asserted-by":"publisher","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":"B77","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200010)43:10<2230::AID-ANR10>3.0.CO;2-8","article-title":"Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis","volume":"43","author":"Jelaska","year":"2000","journal-title":"Arthritis Rheum"},{"key":"B78","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s12891-016-1197-2","article-title":"Early Endothelial Progenitor Cells (eEPCs) in systemic sclerosis (SSc) - dynamics of cellular regeneration and mesenchymal transdifferentiation","volume":"17","author":"Patschan","year":"2016","journal-title":"BMC Musculoskel Dis"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1093\/mr\/road068","article-title":"Efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis and associated interstitial lung disease: A subgroup analysis of a global, randomised, controlled Phase 3 trial","volume":"34","author":"Kuwana","year":"2024","journal-title":"Mod Rheumatol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1007\/s40674-021-00188-9","article-title":"Dysregulation of type 1 interferon signaling in systemic sclerosis: a promising therapeutic target","volume":"7","author":"Wu","year":"2021","journal-title":"Curr Treat Opt Rheum"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.55563\/clinexprheumatol\/s8qcyu","article-title":"A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale","volume":"42","author":"Khanna","year":"2024","journal-title":"Clin Exp Rheumatol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"e85032","DOI":"10.1371\/journal.pone.0085032","article-title":"IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway","volume":"8","author":"Xing","year":"2013","journal-title":"PloS One"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-014-0037-0","article-title":"Early systemic sclerosis: serum profiling of factors involved in endothelial, T-cell, and fibroblast interplay is marked by elevated interleukin-33 levels","volume":"34","author":"Vettori","year":"2014","journal-title":"J Clin Immunol"},{"key":"B84","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/s41598-024-84820-3","article-title":"Common biomarkers of idiopathic pulmonary fibrosis and systemic sclerosis based on WGCNA and machine learning","volume":"15","author":"Shan","year":"2025","journal-title":"Sci Rep-Uk"},{"key":"B85","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jdermsci.2021.07.006","article-title":"Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis","volume":"104","author":"Jiang","year":"2021","journal-title":"J Dermatol Sci"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102444","article-title":"CXCL4 triggers monocytes and macrophages to produce PDGF-BB, culminating in fibroblast activation: Implications for systemic sclerosis","volume":"111","author":"van der Kroef","year":"2020","journal-title":"J Autoimmun"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1468821","article-title":"Efferocytosis dysfunction in CXCL4-induced M4 macrophages: phenotypic insights in systemic sclerosis","volume":"15","author":"Le Tallec","year":"2024","journal-title":"Vitro vivo. Front Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa747","article-title":"Immunoglobulin G of systemic sclerosis patients programs a pro-inflammatory and profibrotic phenotype in monocyte-like THP-1 cells","volume":"60","author":"Murthy","year":"2021","journal-title":"Rheumatology"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.073387","article-title":"Blockade of CD40\/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse","volume":"67","author":"Komura","year":"2008","journal-title":"Ann Rheum Dis"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.13339","article-title":"Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis","volume":"43","author":"Yanaba","year":"2016","journal-title":"J Dermatol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102596","article-title":"Risk of scleroderma according to the type of immune checkpoint inhibitors","volume":"19","author":"Terrier","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B92","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13075-020-2130-5","article-title":"TGFbeta-mediated expression of TGFbeta-activating integrins in SSc monocytes: disturbed activation of latent TGFbeta","volume":"22","author":"van Caam","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1186\/1755-1536-7-13","article-title":"Impaired Cav-1 expression in SSc mesenchymal cells upregulates VEGF signaling: a link between vascular involvement and fibrosis","volume":"7","author":"Cipriani","year":"2014","journal-title":"Fibrogenesis Tissue Repair"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2022.103185","article-title":"T cell abnormalities in systemic sclerosis","volume":"21","author":"Jin","year":"2022","journal-title":"Autoimmun Rev"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/0190-9622(92)70165-c","article-title":"Expression of adhesion proteins involved in cell-cell and cell-matrix interactions in the skin of patients with progressive systemic sclerosis","volume":"27","author":"Gruschwitz","year":"1992","journal-title":"J Am Acad Dermatol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.14914","article-title":"Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis","volume":"46","author":"Fukui","year":"2019","journal-title":"J Dermatol"},{"key":"B97","doi-asserted-by":"publisher","first-page":"R165","DOI":"10.1186\/ar4349","article-title":"Decreased expression of the endothelial cell-derived factor EGFL7 in systemic sclerosis: potential contribution to impaired angiogenesis and vasculogenesis","volume":"15","author":"Manetti","year":"2013","journal-title":"Arthritis Res Ther"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.161092","article-title":"Fli1 deficiency induces CXCL6 expression in dermal fibroblasts and endothelial cells, contributing to the development of fibrosis and vasculopathy in systemic sclerosis","volume":"44","author":"Taniguchi","year":"2017","journal-title":"J Rheumatol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2000.01115.x","article-title":"Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonary fibrosis","volume":"119","author":"Ihn","year":"2000","journal-title":"Clin Exp Immunol"},{"key":"B100","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.vph.2013.05.002","article-title":"Agonistic anti-ICAM-1 antibodies in scleroderma: activation of endothelial pro-inflammatory cascades","volume":"59","author":"Wolf","year":"2013","journal-title":"Vasc Pharmacol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111793","article-title":"Autoantibodies from patients with scleroderma renal crisis promote PAR-1 receptor activation and IL-6 production in endothelial cells","volume":"22","author":"Simon","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B102","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1002\/art.22698","article-title":"Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis","volume":"56","author":"Cipriani","year":"2007","journal-title":"Arthritis Rheum"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.05.024","article-title":"The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review","volume":"16","author":"Mostmans","year":"2017","journal-title":"Autoimmun Rev"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26062699","article-title":"Lymphomonocytic extracellular vesicles influence fibroblast proliferation and collagen production in systemic sclerosis","volume":"26","author":"Argentino","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12020295","article-title":"Exploring the utility of circulating endothelial cell-derived extracellular vesicles as markers of health and damage of vasal endothelium in systemic sclerosis patients treated with iloprost","volume":"12","author":"Argentino","year":"2024","journal-title":"Biomedicines"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1492821","article-title":"Mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis: role and therapeutic directions","volume":"12","author":"Wang","year":"2024","journal-title":"Front Cell Dev Biol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.3390\/ph18020259","article-title":"Extracellular vesicles as a potential biomarker of pulmonary arterial hypertension in systemic sclerosis","volume":"18","author":"Tonello","year":"2025","journal-title":"Pharmaceuticals-Base"},{"key":"B108","doi-asserted-by":"publisher","first-page":"e2696","DOI":"10.1371\/journal.pone.0002696","article-title":"Molecular subsets in the gene expression signatures of scleroderma skin","volume":"3","author":"Milano","year":"2008","journal-title":"PloS One"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215894","article-title":"Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile","volume":"79","author":"Skaug","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B110","doi-asserted-by":"publisher","first-page":"4949","DOI":"10.1038\/s41467-025-60034-7","article-title":"Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis","volume":"16","author":"Shimagami","year":"2025","journal-title":"Nat Commun"},{"key":"B111","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1097\/BOR.0000000000000656","article-title":"Biomarkers in systemic sclerosis","volume":"31","author":"Skaug","year":"2019","journal-title":"Curr Opin Rheumatol"},{"key":"B112","doi-asserted-by":"publisher","first-page":"1245856039","DOI":"10.1177\/23971983251357991","article-title":"The serum levels of specific autoantibodies in systemic sclerosis predict a more severe skin involvement","author":"Dengler","year":"2025","journal-title":"J Scleroderma Relat"},{"key":"B113","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1515\/rir-2024-0013","article-title":"Biomarkers in the evaluation of cardiac involvement in systemic sclerosis","volume":"5","author":"Masri","year":"2024","journal-title":"Rheumatol Immunol Res"},{"key":"B114","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ejim.2018.10.013","article-title":"Cardiac troponin T and NT-proBNP as diagnostic and prognostic biomarkers of primary cardiac involvement and disease severity in systemic sclerosis: A prospective study","volume":"60","author":"Bosello","year":"2019","journal-title":"Eur J Intern Med"},{"key":"B115","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1136\/thorax-2022-219226","article-title":"Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses","volume":"78","author":"Fields","year":"2023","journal-title":"Thorax"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/art.40455","article-title":"Skin gene expression is prognostic for the trajectory of skin disease in patients with diffuse cutaneous systemic sclerosis","volume":"70","author":"Stifano","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2023.109695","article-title":"Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis","volume":"254","author":"Sheng","year":"2023","journal-title":"Clin Immunol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00251-6","article-title":"Exploiting a unified vascular framework to predict organ-specific complications and accomplish disease modification in systemic sclerosis","volume":"7","author":"Pauling","year":"2025","journal-title":"Lancet Rheumatol"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(21)00107-7","article-title":"Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial","volume":"3","author":"Ebata","year":"2021","journal-title":"Lancet Rheumatol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(22)00131-X","article-title":"Safety and efficacy of rituximab in systemic sclerosis (DESIRES): open-label extension of a double-blind, investigators-initiated, randomised, placebo-controlled trial","volume":"4","author":"Ebata","year":"2022","journal-title":"Lancet Rheumatol"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae280","article-title":"Rituximab retention rate in systemic sclerosis: a long term real-life multicentre study","volume":"64","author":"De Luca","year":"2025","journal-title":"Rheumatology"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1002\/art.40358","article-title":"Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial","volume":"70","author":"Gordon","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1002\/art.41055","article-title":"Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial","volume":"72","author":"Khanna","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30237-X","article-title":"Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial","volume":"2","author":"Chung","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"B125","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1177\/2397198319865367","article-title":"The JAK\/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib","volume":"5","author":"Wang","year":"2020","journal-title":"J Scleroderma Relat"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa613","article-title":"Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis","volume":"60","author":"You","year":"2021","journal-title":"Rheumatology"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-023-06660-2","article-title":"Retrospective comparative study of the efficacy of JAK inhibitor (tofacitinib) in the treatment of systemic sclerosis-associated interstitial lung disease","volume":"42","author":"Junfei","year":"2023","journal-title":"Clin Rheumatol"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1080\/03009742.2017.1387673","article-title":"Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis","volume":"47","author":"Komai","year":"2018","journal-title":"Scand J Rheumatol"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.859330","article-title":"JAK1\/2 inhibitor baricitinib improves skin fibrosis and digital ulcers in systemic sclerosis","volume":"9","author":"Hou","year":"2022","journal-title":"Front Med-Lausanne"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(24)00282-0","article-title":"CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series","volume":"7","author":"Auth","year":"2025","journal-title":"Lancet Rheumatol"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.06.027","article-title":"Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis","volume":"187","author":"Wang","year":"2024","journal-title":"Cell"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.07.007","article-title":"iPSC-derived CAR-NK cells: Off-the-shelf cellular therapy for systemic sclerosis","volume":"188","author":"Daher","year":"2025","journal-title":"Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1713221\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T06:43:06Z","timestamp":1772433786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1713221\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":132,"alternative-id":["10.3389\/fimmu.2026.1713221"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1713221","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]},"article-number":"1713221"}}