{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:58:34Z","timestamp":1785560314433,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008061","name":"Fundaci\u00f3n Mutua Madrile\u00f1a","doi-asserted-by":"publisher","award":["AP177092021"],"award-info":[{"award-number":["AP177092021"]}],"id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]},{"award":["AP177092021"],"award-info":[{"award-number":["AP177092021"]}],"id":[{"id":"https:\/\/ror.org\/00skv9577","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by \u03b1-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Beyond substrate storage, low-grade inflammation and complement activation have been increasingly implicated in FD pathogenesis, yet a comprehensive characterization of this immuno-inflammatory profile is lacking. In this exploratory cross-sectional study, fifteen patients with FD and fifteen age- and sex-matched healthy controls (HCs) were assessed using a broad panel of systemic inflammatory, humoral immunity\/complement, hematological, and endothelial biomarkers, integrated through univariate analysis (Cliff\u2019s delta, \u03b4), penalized least absolute shrinkage and selection operator (LASSO) regression, and unsupervised hierarchical clustering. Fibrinogen (\u03b4 = 0.60, 95% confidence interval (CI) 0.24\u20130.88), sTNFR2 (\u03b4 = 0.48, 95% CI 0.08\u20130.80), complement C4 (\u03b4 = 0.53, 95% CI 0.13\u20130.84), and lymphocyte count (\u03b4 = 0.52, 95% CI 0.15\u20130.85) showed the largest between-group effect sizes among the immuno-inflammatory biomarkers assessed, with higher levels in FD. Fibrinogen and sTNFR2 were the most stable predictors in LASSO bootstrap resampling (selected in 75.0% and 69.5% of iterations, respectively), and unsupervised clustering segregated FD from HCs with high accuracy (90% FD enrichment in the high-biomarker cluster; p &lt; 0.001). These convergent findings indicate that FD is characterized by a distinct low-grade immuno-inflammatory profile dominated by innate immune and complement activation.<\/jats:p>","DOI":"10.3390\/ijms27156850","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:00Z","timestamp":1785428100000},"page":"6850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immuno-Inflammatory Profiling and Complement Activation in Fabry Disease: A Cross-Sectional Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Mercedes","family":"Pe\u00f1a-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4522-8511","authenticated-orcid":false,"given":"Nuria","family":"Bara-Ledesma","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"},{"name":"Group of Multisystemic Diseases, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7378-4868","authenticated-orcid":false,"given":"Martin","family":"Fabregate","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Group of Multisystemic Diseases, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Morales Conejo","sequence":"additional","affiliation":[{"name":"Unit for Congenital Metabolic Diseases and Other Rare Diseases, Internal Medicine Department, Reference Center for Inherited Metabolic Disease-MetabERN, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Dom\u00ednguez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2433-7751","authenticated-orcid":false,"given":"Borja","family":"Merino-Ortiz","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"},{"name":"CSUR de Enfermedades Metab\u00f3licas, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0340-4580","authenticated-orcid":false,"given":"Sinziana","family":"Stanescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"},{"name":"CSUR de Enfermedades Metab\u00f3licas, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Metabolic Diseases Unit, Department of Pediatrics, European Reference Network for Hereditary Metabolic Disorders (MetabERN), Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1785-4988","authenticated-orcid":false,"given":"Pedro","family":"Ruiz-Sala","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM), Autonomous University of Madrid (UAM), IdiPaz, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7367-9523","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Gonz\u00e1lez Garc\u00eda","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"},{"name":"Group of Multisystemic Diseases, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-8956","authenticated-orcid":false,"given":"Amaya","family":"Belanger-Quintana","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28805 Alcal\u00e1 de Henares, Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"CSUR de Enfermedades Metab\u00f3licas, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Metabolic Diseases Unit, Department of Pediatrics, European Reference Network for Hereditary Metabolic Disorders (MetabERN), Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, 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Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1001\/jama.281.3.249","article-title":"Prevalence of Lysosomal Storage Disorders","volume":"281","author":"Meikle","year":"1999","journal-title":"JAMA"},{"key":"ref_3","unstructured":"Valle, D.L., Antonarakis, S., Ballabio, A., Beaudet, A.L., and Mitchell, G.A. (2001). \u03b1-Galactosidase A Deficiency: Fabry Disease. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1681\/ASN.2016090964","article-title":"Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study","volume":"28","author":"Arends","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rydzek, J., Muzyka, A., Majcherczyk, K., Soczy\u0144ska, J., Gawe\u0142czyk, W., \u017bo\u0142yniak, M., and Wo\u017aniak, S. (2026). Fabry Disease: A Focus on the Role of Oxidative Stress. Antioxidants, 15.","DOI":"10.3390\/antiox15020168"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Simonetta, I., Baglio, I., and Tuttolomondo, A. (2026). Molecular, Metabolic and Inflammatory Patterns Involved in Pathogenesis of Anderson-Fabry Disease. Cells, 15.","DOI":"10.3390\/cells15050443"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e009098","DOI":"10.1161\/JAHA.118.009098","article-title":"Elevated Inflammatory Plasma Biomarkers in Patients With Fabry Disease: A Critical Link to Heart Failure With Preserved Ejection Fraction","volume":"7","author":"Yogasundaram","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yuan, Y., Zhao, Y., Li, F., Ling, C., Wu, Y., Ma, W., Wang, Z., Yuan, Y., Hao, H., and Zhang, W. (2024). Inflammatory Cytokine Expression in Fabry Disease: Impact of Disease Phenotype and Alterations under Enzyme Replacement Therapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1367252"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ymgme.2013.02.003","article-title":"Fabry Disease Peripheral Blood Immune Cells Release Inflammatory Cytokines: Role of Globotriaosylceramide","volume":"109","author":"Mucci","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Laffer, B., Lenders, M., Ehlers-Jeske, E., Heidenreich, K., Brand, E., and K\u00f6hl, J. (2024). Complement Activation and Cellular Inflammation in Fabry Disease Patients despite Enzyme Replacement Therapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1307558"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Magnusen, A.F., and Pandey, M.K. (2024). Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212252"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pandey, M.K. (2023). Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases. Biomedicines, 11.","DOI":"10.3390\/biomedicines11041067"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ymgme.2017.09.004","article-title":"Contribution of Inflammatory Pathways to Fabry Disease Pathogenesis","volume":"122","author":"Rozenfeld","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Faro, D.C., Di Pino, F.L., and Monte, I.P. (2024). Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158273"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Biddeci, G., Spinelli, G., Colomba, P., Duro, G., Giacalone, I., and Di Blasi, F. (2025). Fabry Disease Beyond Storage: The Role of Inflammation in Disease Progression. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157054"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1007\/s10157-021-02058-z","article-title":"Pathology and Pathogenic Pathways in Fabry Nephropathy","volume":"25","author":"Feriozzi","year":"2021","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_17","first-page":"1221.e1","article-title":"Evaluation of Proinflammatory Prognostic Biomarkers for Fabry Cardiomyopathy With Enzyme Replacement Therapy","volume":"32","author":"Chen","year":"2016","journal-title":"Can. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Paccalet, A., Crola Da Silva, C., Mechtouff, L., Amaz, C., Varillon, Y., de Bourguignon, C., Cartier, R., Prieur, C., Tomasevic, D., and Genot, N. (2021). Serum Soluble Tumor Necrosis Factor Receptors 1 and 2 Are Early Prognosis Markers After ST-Segment Elevation Myocardial Infarction. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.656928"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Iversen, P.L., Kipshidze, N., Kipshidze, N., Dangas, G., Ramacciotti, E., Kakabadze, Z., and Fareed, J. (2023). A Novel Therapeutic Vaccine Targeting the Soluble TNF\u03b1 Receptor II to Limit the Progression of Cardiovascular Disease: AtheroVaxTM. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1206541"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109204","DOI":"10.1016\/j.jdiacomp.2025.109204","article-title":"Soluble Tumor Necrosis Factor Receptors (STNFRs) as Biomarkers for Diabetic Kidney Disease","volume":"40","author":"Moroney","year":"2026","journal-title":"J. Diabetes Complicat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1136\/ard-2022-223757","article-title":"Distinct Immune Modulatory Roles of Regulatory T Cells in Gut versus Joint Inflammation in TNF-Driven Spondyloarthritis","volume":"82","author":"Venken","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"280","DOI":"10.2215\/CJN.07360715","article-title":"Residual Associations of Inflammatory Markers with EGFR after Accounting for Measured GFR in a Community-Based Cohort without CKD","volume":"11","author":"Schei","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1136\/jmedgenet-2017-104704","article-title":"Fabry Disease: Characterisation of the Plasma Proteome Pre- and Post-Enzyme Replacement Therapy","volume":"54","author":"Heo","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kurdi, H., Lavalle, L., Moon, J.C.C., and Hughes, D. (2024). Inflammation in Fabry Disease: Stages, Molecular Pathways, and Therapeutic Implications. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1420067"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.immuni.2008.02.001","article-title":"Locally Produced Complement Fragments C5a and C3a Provide Both Costimulatory and Survival Signals to Naive CD4+ T Cells","volume":"28","author":"Strainic","year":"2008","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Breznik, N., Levstek, T., Vujkovac, B., Cokan Vujkovac, A., and Trebu\u0161ak Podkraj\u0161ek, K. (2025). Transcriptomic Approach in Understanding Fabry Nephropathy: A Review of the Literature and Proof-of-Concept. Genes, 16.","DOI":"10.3390\/genes16050601"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Coelho-Ribeiro, B., Silva, H.G., Sampaio-Marques, B., Fraga, A.G., Azevedo, O., Pedrosa, J., and Ludovico, P. (2024). Inflammation and Exosomes in Fabry Disease Pathogenesis. Cells, 13.","DOI":"10.3390\/cells13080654"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ymgme.2017.07.002","article-title":"Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease","volume":"123","author":"Nowak","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109110","DOI":"10.1016\/j.ymgme.2025.109110","article-title":"The use and performance of lyso-Gb3 for the diagnosis and monitoring of Fabry disease: A systematic literature review","volume":"145","author":"Ramaswami","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_30","first-page":"1","article-title":"Using Cliff\u2019s Delta as a Non-Parametric Effect Size Measure: An Accessible Web App and R Tutorial","volume":"29","author":"Meissel","year":"2024","journal-title":"Pract. Assess. Res. 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