{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:57Z","timestamp":1787028657040,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,16]],"date-time":"2025-03-16T00:00:00Z","timestamp":1742083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease characterised by fibrosis, vasculopathy, and immune dysfunction. Silica exposure has been associated with a more aggressive phenotype of the disease, including diffuse cutaneous involvement and interstitial lung disease. This study aims to identify proteomic differences between SSc patients exposed to silica and those not exposed to silica. Methods: An observational study of 32 SSc patients (11 silica-exposed and 21 non-exposed) was performed, with occupational history and quantitative proteomic analysis using SWATH-MS mass spectrometry. Differentially expressed proteins were analysed, and functional pathway enrichment was performed. Results: Eight proteins showed significant differences between groups, all with reduced levels in silica-exposed patients: adiponectin, immunoglobulins (IGLV3-19, IGLV2-18), complement C2, alpha-2-macroglobulin, vitronectin, cytoplasmic actin 2, and pigment epithelium-derived factor. Alterations in pathways related to fibrinolysis, complement activation, and inflammation were highlighted, suggesting that silica exposure may influence the pathogenesis of SSc and worsen its clinical course. Conclusions: This study supports the hypothesis that silica exposure is not only a triggering factor for SSc, but is also modulating its progression through inflammatory, procoagulant, and fibrotic pathways. The identification of proteomic biomarkers could contribute to the phenotypic classification of patients and the development of personalised therapies. Future studies should expand the cohort and further investigate the functional mechanisms of these proteins in SSc.<\/jats:p>","DOI":"10.3390\/jcm14062019","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T04:29:28Z","timestamp":1742185768000},"page":"2019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Serum Proteomic Markers in Patients with Systemic Sclerosis in Relation to Silica Exposure"],"prefix":"10.3390","volume":"14","author":[{"given":"Mayka","family":"Freire","sequence":"first","affiliation":[{"name":"Unidad de Enfermedades Sist\u00e9micas e Inmunopatolog\u00eda, Servicio de Medicina Interna, Hospital Cl\u00ednico de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Sope\u00f1a","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Sist\u00e9micas e Inmunopatolog\u00eda, Servicio de Medicina Interna, Hospital Cl\u00ednico de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7615-3079","authenticated-orcid":false,"given":"Susana","family":"Bravo","sequence":"additional","affiliation":[{"name":"Laboratorio de Prote\u00f3mica, Instituto de Investigaci\u00f3n Sanitaria de Santiago, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9161-0124","authenticated-orcid":false,"given":"Carlos","family":"Spuch","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Sa\u00fade-Universidade de Vigo), 36312 Vigo, Spain"},{"name":"CIBERSAM (Network Biomedical Research Center on Mental Health), 28029 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n de Atenci\u00f3n Primaria en Adicciones (RIAPAD), 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Argibay","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Autoinmunes Sist\u00e9micas y Trombosis, Servicio de Medicina Interna, Complejo Hospitalario Universitario de Vigo, 36312 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melania","family":"Est\u00e9vez","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Autoinmunes Sist\u00e9micas y Trombosis, Servicio de Medicina Interna, Complejo Hospitalario Universitario de Vigo, 36312 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Pena","sequence":"additional","affiliation":[{"name":"Laboratorio de Prote\u00f3mica, Instituto de Investigaci\u00f3n Sanitaria de Santiago, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart\u00edn","family":"Naya","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Sist\u00e9micas e Inmunopatolog\u00eda, Servicio de Medicina Interna, Hospital Cl\u00ednico de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Lama","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Sist\u00e9micas e Inmunopatolog\u00eda, Servicio de Medicina Interna, Hospital Cl\u00ednico de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Gonz\u00e1lez-Quintela","sequence":"additional","affiliation":[{"name":"Departamento de Psiquiatr\u00eda, Radiolog\u00eda, Salud P\u00fablica, Enfermer\u00eda y Medicina, Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1097\/MD.0b013e318189372f","article-title":"Systemic sclerosis in northwestern Spain: A 19-year epidemiologic study","volume":"87","author":"Llorca","year":"2008","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1136\/ard.2009.114264","article-title":"Causes and risk factors for death in systemic sclerosis: A study from the EULAR Scleroderma Trials and Research (EUSTAR) database","volume":"69","author":"Tyndall","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1007\/s12016-013-8392-9","article-title":"The sex bias in systemic sclerosis: On the possible mechanisms underlying the female disease preponderance","volume":"47","author":"Skarmoutsou","year":"2014","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.jaad.2014.11.027","article-title":"Association of occupational exposure with features of systemic sclerosis","volume":"72","author":"Marie","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.semarthrit.2015.06.004","article-title":"Clinical peculiarities of patients with scleroderma exposed to silica: A systematic review of the literature","volume":"45","author":"Freire","year":"2015","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.semarthrit.2018.06.009","article-title":"High serum levels of silica nanoparticles in systemic sclerosis patients with occupational exposure: Possible pathogenetic role in disease phenotypes","volume":"48","author":"Ferri","year":"2018","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1097\/ACI.0000000000000350","article-title":"Silicosis and autoimmunity","volume":"17","author":"Lee","year":"2017","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3389\/fimmu.2016.00097","article-title":"Silica, Silicosis, and Autoimmunity","volume":"7","author":"Pollard","year":"2016","journal-title":"Front Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chairta, P.P., Nicolaou, P., and Christodoulou, K. (2023). Enrichr in silico analysis of MS-based extracted candidate proteomic biomarkers highlights pathogenic pathways in systemic sclerosis. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-29054-5"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"2013 classification criteria for systemic sclerosis: An American college of rheumatology\/European league against rheumatism collaborative initiative","volume":"72","author":"Khanna","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_13","unstructured":"Arana, V., Arias, M., Ariza, M., Arzallus, M., Cabrerizo, J.I., Carballo, M., Fern\u00e1ndez, P., Fern\u00e1ndez, A., Fern\u00e1ndez, E., and Freijo, A. (2024, March 13). Protocolo de Vigilancia Sanitaria Espec\u00edfica. Silicosis Comisi\u00f3n de Salud P\u00fablica. Consejo Interterritorial del Sistema Nacional de Salud. MInisterio de Sanidad. Gobierno de Espa\u00f1a. Available online: https:\/\/www.sanidad.gob.es\/ciudadanos\/saludAmbLaboral\/docs\/silicosis.pdf."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(12)60235-9","article-title":"Silicosis","volume":"379","author":"Leung","year":"2012","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1289\/ehp.0800144","article-title":"Pneumoconiosis from agricultural dust exposure among young California farmworkers","volume":"117","author":"Schenker","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_16","unstructured":"Ferrero Arias, \u00c1., Rubio Navas, J., P\u00e9rez Cerd\u00e1n, F., Baltuille Mart\u00edn, J.M., and Fern\u00e1ndez Su\u00e1rez, J. (2008). Mapa de Rocas y Minerales Industriales de Galicia, Instituto Geol\u00f3gico y Minero de Espa\u00f1a."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Alonso-Sampedro, M., Fe\u00e1s, X., Bravo, S.B., Chantada-V\u00e1zquez, M.P., and Vidal, C. (2023). Proteomics of Vespa velutina nigrithorax Venom Sac Queens and Workers: A Quantitative SWATH-MS Analysis. Toxins, 15.","DOI":"10.3390\/toxins15040266"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fe\u00e1s, X., Alonso-Sampedro, M., Bravo, S.B., and Vidal, C. (2024). Peeking into the Stingers: A Comprehensive SWATH-MS Study of the European Hornet Vespa crabro (Linnaeus, 1758) (Hymenoptera: Vespidae) Venom Sac Extracts. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202403.0189.v1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez, J.V., Bravo, S.B., Chantada-V\u00e1zquez, M.P., Pena, C., Col\u00f3n, C., Tomatsu, S., Otero-Espinar, F.J., and Couce, M.L. (2024). Morquio A Syndrome: Identification of Differential Patterns of Molecular Pathway Interactions in Bone Lesions. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202401.2246.v1"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Casado-Fern\u00e1ndez, L., Laso-Garc\u00eda, F., Piniella, D., Frutos, M.C.G.-D., Otero-Ortega, L., Bravo, S.-B., Fuentes-Gimeno, B., Docando, F., Alonso-L\u00f3pez, E., and Ruiz-Ares, G. (2024). The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery. Neurobiol. Dis., 201.","DOI":"10.1016\/j.nbd.2024.106665"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101962","DOI":"10.1016\/j.molmet.2024.101962","article-title":"Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice","volume":"85","author":"Fondevila","year":"2024","journal-title":"Mol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111108","DOI":"10.1016\/j.isci.2024.111108","article-title":"Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke","volume":"27","author":"Akkoc","year":"2024","journal-title":"iScience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.1038\/s41467-024-47751-1","article-title":"dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe","volume":"15","author":"Rodrigues","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Iglesias, G.T., L\u00f3pez-Molina, M., Botella, L., Laso-Garc\u00eda, F., Chamorro, B., Fern\u00e1ndez-Fournier, M., Puertas, I., Bravo, S.B., Alonso-L\u00f3pez, E., and D\u00edez-Tejedor, E. (2024). Differential Protein Expression in Extracellular Vesicles Defines Treatment Responders and Non-Responders in Multiple Sclerosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910761"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1111\/all.16327","article-title":"Exploring CD26\u2212\/lo subpopulations of lymphocytes in asthma phenotype and severity: A novel CD4+ T cell subset expressing archetypical granulocyte proteins","volume":"79","author":"Bravo","year":"2024","journal-title":"Allergy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/nmeth.2702","article-title":"Mapping differential interactomes by affinity purification coupled with data-independent mass spectrometry acquisition","volume":"10","author":"Lambert","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_27","first-page":"135","article-title":"Treatment of digital ulcers in systemtic sclerosis with endothelin-1 receptor antagonist (bosentan)","volume":"59","author":"Riccardi","year":"2007","journal-title":"Reumatismo"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1080\/08923973.2024.2445731","article-title":"Pesticide exposure promotes disease activity by decreasing lymphoproliferative activity and increasing IL-4 production in systemic sclerosis patients","volume":"47","author":"Alsulimani","year":"2025","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"111154","DOI":"10.1016\/j.humimm.2024.111154","article-title":"Elevated Interleukin-21 expression is correlated with systemic sclerosis\u2019 severity in Tunisian patients","volume":"85","author":"Dlala","year":"2024","journal-title":"Hum. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"259","DOI":"10.31083\/j.fbl2907259","article-title":"Inflammatory Response of Monocytes\/Macrophages in Patients with Systemic Sclerosis","volume":"29","author":"Kirichenko","year":"2024","journal-title":"Front. Biosci.-Landmark"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Brezovec, N., Perdan-Pirkmajer, K., \u010cu\u010dnik, S., Sodin-\u0161emrl, S., Varga, J., and Lakota, K. (2021). Adiponectin deregulation in systemic autoimmune rheumatic diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084095"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1111\/j.1600-0625.2011.01310.x","article-title":"Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients","volume":"20","author":"Arakawa","year":"2011","journal-title":"Exp. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cyto.2018.11.013","article-title":"Adipokine expression in systemic sclerosis lung and gastrointestinal organ involvement","volume":"117","author":"Neumann","year":"2019","journal-title":"Cytokine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"R102","DOI":"10.1186\/ar3827","article-title":"Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: Potential utility as biomarker?","volume":"14","author":"Lakota","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_35","first-page":"156","article-title":"Circulating adipokines and organ involvement in patients with systemic sclerosis","volume":"40","author":"Katulska","year":"2015","journal-title":"Acta Reum. Port."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1002\/art.41418","article-title":"Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease","volume":"72","author":"Ryu","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.2147\/JIR.S431628","article-title":"Diagnostic Values of METTL1-Related Genes and Immune Characteristics in Systemic Lupus Erythematosus","volume":"16","author":"Liu","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/BF02507111","article-title":"Plasma concentration of total and transformed alpha 2-macroglobulin in systemic sclerosis","volume":"288","author":"Birkenmeier","year":"1996","journal-title":"Arch. Dermatol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.17219\/acem\/68627","article-title":"Serum osteopontin and vitronectin levels in systemic sclerosis","volume":"26","author":"Gundogdu","year":"2017","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"F1244","DOI":"10.1152\/ajprenal.00701.2010","article-title":"Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease","volume":"300","author":"Rassa","year":"2011","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11926-020-00970-z","article-title":"Skin histology in systemic sclerosis: A relevant clinical biomarker","volume":"23","author":"Showalter","year":"2020","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.2353\/ajpath.2010.091095","article-title":"Proteomic analysis identification of a pattern of shared alterations in the secretome of dermal fibroblasts from systemic sclerosis and nephrogenic systemic fibrosis","volume":"177","author":"Shaw","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/annrheumdis-2017-212120","article-title":"Scleroderma fibroblasts suppress angiogenesis via TGF-\u03b2\/caveolin-1 dependent secretion of pigment epithelium-derived factor","volume":"77","author":"Liakouli","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Tsai, T.-H., Shih, S.-C., Ho, T.-C., Ma, H.-I., Liu, M.-Y., Chen, S.-L., and Tsao, Y.-P. (2014). Pigment epithelium-derived factor 34-mer peptide prevents liver fibrosis and hepatic stellate cell activation through down-regulation of the PDGF receptor. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095443"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.rdc.2007.12.001","article-title":"The many faces of scleroderma","volume":"34","author":"Steen","year":"2008","journal-title":"Rheum. Dis. Clin. N. Am."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/6\/2019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:39Z","timestamp":1760028879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/6\/2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,16]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["jcm14062019"],"URL":"https:\/\/doi.org\/10.3390\/jcm14062019","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,16]]}}}