{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:13:38Z","timestamp":1780582418093,"version":"3.54.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"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. Neurol."],"abstract":"<jats:p>Natalizumab (NTZ) can reactivate human polyomavirus John Cunningham polyomavirus (JCPyV) latent infection and lead to progressive multifocal leukoencephalopathy (PML). NTZ modulates the expression of microRNA-126-3p (miR-126-3p) and its target genes, <jats:italic>Spi-B, POU2AF1<\/jats:italic>, and vascular cell adhesion molecule-1 (VCAM-1); Spi-B protein binds the JCPyV regulatory region, initiating early gene transcription. This paper is aimed to evaluate the miR-126-3p and soluble (s)VCAM-1 concentration, <jats:italic>Spi-B<\/jats:italic>\/<jats:italic>POU2AF1<\/jats:italic> gene expression, and JCPyV activity in patients with multiple sclerosis (MS) before and during 2-years NTZ. Serum miR-126-3p and sVCAM-1 concentration was measured before NTZ and after 1, 12, and 24 months of treatment in 22 MS subjects, 1 patient who developed PML, and 29 healthy controls (HCs). The <jats:italic>Spi-B<\/jats:italic> and <jats:italic>POU2AF1<\/jats:italic> expression in blood was analyzed at baseline and at month 24 in 13 patients with MS; results were clusterized based on JCPyV activity. miR-126-3p was significantly downregulated in MS before and during NTZ but was greatly increased in the PML patient. sVCAM-1 concentration was comparable in MS and HCs, and was reduced by NTZ in MS and PML. <jats:italic>Spi-B\/POU2AF1<\/jats:italic> expression was significantly increased in MS at baseline and was upregulated by NTZ, particularly in JCPyV-infected patients in whom JCPyV reactivation was detected. Taken together, the results suggest that the modulation of the miR-126-3p\/<jats:italic>POU2AF1\/Spi-B<\/jats:italic> axis associates with JCPyV activity in NTZ-treated patients with MS.<\/jats:p>","DOI":"10.3389\/fneur.2022.819911","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T10:04:57Z","timestamp":1646993097000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Alterations of the miR-126-3p\/POU2AF1\/Spi-B Axis and JCPyV Reactivation in Multiple Sclerosis Patients Receiving Natalizumab"],"prefix":"10.3389","volume":"13","author":[{"given":"Roberta","family":"Mancuso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Agostini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambra","family":"Hernis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Caputo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Galimberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Scarpini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"276","DOI":"10.3390\/cells9020276","article-title":"miRNAs as biomarkers in disease: latest findings regarding their role in diagnosis and prognosis","volume":"9","author":"Condrat","year":"2020","journal-title":"Cells."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","article-title":"Multiple sclerosis","volume":"372","author":"Compston","year":"2008","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1111\/joim.12203","article-title":"Established and novel disease-modifying treatments in multiple sclerosis","volume":"275","author":"Cross","year":"2014","journal-title":"J Intern Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1056\/NEJMoa044397","article-title":"A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis","volume":"354","author":"Polman","year":"2006","journal-title":"N Engl J Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jneuroim.2010.07.012","article-title":"Natalizumab treatment reduces endothelial activity in MS patients","volume":"227","author":"Millonig","year":"2010","journal-title":"J Neuroimmunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1001\/archneur.63.10.1383","article-title":"Altered CD4+\/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis","volume":"63","author":"Stuve","year":"2006","journal-title":"Arch Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e223","DOI":"10.1212\/NXI.0000000000000223","article-title":"Natalizumab-induced POU2AF1\/Spi-B upregulation: A possible route for PML development","volume":"3","author":"Meira","year":"2016","journal-title":"Neurol Neuroimmunol Neuroinflamm."},{"key":"B8","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1146\/annurev.med.080708.082655","article-title":"Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies","volume":"61","author":"Major","year":"2010","journal-title":"Annu Rev Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1128\/CMR.05031-11","article-title":"Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain","volume":"25","author":"Ferenczy","year":"2012","journal-title":"Clin Microbiol Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1007\/s11481-010-9203-1","article-title":"Molecular regulation of JC virus tropism: insights into potential therapeutic targets for progressive multifocal leukoencephalopathy","volume":"5","author":"Marshall","year":"2010","journal-title":"J Neuroimmune Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"10448","DOI":"10.1128\/JVI.00614-10","article-title":"Rearranged JC virus noncoding control regions found in progressive multifocal leukoencephalopathy patient samples increase virus early gene expression and replication rate","volume":"84","author":"Gosert","year":"2010","journal-title":"J Virol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1177\/1352458515578771","article-title":"miRNA in multiple sclerosis: search for novel biomarkers","volume":"21","author":"Gandhi","year":"2015","journal-title":"Mult Scler."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1177\/1352458514534513","article-title":"Blood miRNA expression pattern is a possible risk marker for natalizumab-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients","volume":"20","author":"Mu\u00f1oz-Culla","year":"2014","journal-title":"Mult Scler."},{"key":"B14","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.jneuroim.2007.11.007","article-title":"Natalizumab alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients","volume":"194","author":"Lindberg","year":"2008","journal-title":"J Neuroimmunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1002\/ana.22366","article-title":"Diagnostic criteria for multiple sclerosis: 2010 revision to the McDonald criteria","volume":"69","author":"Polman","year":"2011","journal-title":"Ann Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1186\/1479-5876-10-248","article-title":"JC virus detection and JC virus-specific immunity in natalizumab-treated multiple sclerosis patients","volume":"10","author":"Mancuso","year":"2012","journal-title":"J Transl Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.2217\/imt.13.155","article-title":"Partial recovery after severe immune reconstitution inflammatory syndrome in a multiple sclerosis patient with progressive multifocal leukoencephalopathy","volume":"6","author":"Calvi","year":"2014","journal-title":"Immunotherapy."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0153200","DOI":"10.1371\/journal.pone.0153200","article-title":"Comparison of methodologies to detect low levels of hemolysis in serum for accurate assessment of serum microRNAs","volume":"11","author":"Shah","year":"2016","journal-title":"PLoS ONE."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0130715","DOI":"10.1371\/journal.pone.0130715","article-title":"Indoleamine 2,3 Dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis","volume":"10","author":"Mancuso","year":"2015","journal-title":"PLoS ONE."},{"key":"B20","doi-asserted-by":"publisher","first-page":"R19","DOI":"10.1186\/gb-2007-8-2-r19","article-title":"qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data","volume":"8","author":"Hellemans","year":"2007","journal-title":"Genome Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/ana.22128","article-title":"Anti-JC virus antibodies: implications for PML risk stratification","volume":"68","author":"Gorelik","year":"2010","journal-title":"Ann Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1002\/ana.24286","article-title":"Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy","volume":"76","author":"Plavina","year":"2014","journal-title":"Ann Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/S1474-4422(10)70028-4","article-title":"Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases","volume":"9","author":"Clifford","year":"2010","journal-title":"Lancet Neurol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.msard.2016.09.001","article-title":"Soluble serum VCAM-1, whole blood mRNA expression and treatment response in natalizumab-treated multiple sclerosis","volume":"10","author":"Petersen","year":"2016","journal-title":"Mult Scler Relat Disord."},{"key":"B25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s12948-018-0089-4","article-title":"Involvement of miR-126 in autoimmune disorders","volume":"16","author":"Casciaro","year":"2018","journal-title":"Clin Mol Allergy."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e12132","DOI":"10.1371\/journal.pone.0012132","article-title":"MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood","volume":"5","author":"Cox","year":"2010","journal-title":"PLoS ONE."},{"key":"B27","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jneuroim.2018.01.005","article-title":"Immune-related miRNA expression patterns in peripheral blood mononuclear cells differ in multiple sclerosis relapse and remission","volume":"317","author":"Baulina","year":"2018","journal-title":"J Neuroimmunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1038\/s41598-019-38505-x","article-title":"Normalization strategies differently affect circulating miRNA profile associated with the training status","volume":"9","author":"Faraldi","year":"2019","journal-title":"Sci Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e30679","DOI":"10.1371\/journal.pone.0030679","article-title":"The majority of microRNAs detectable in serum and saliva is concentrated in exosomes","volume":"7","author":"Gallo","year":"2012","journal-title":"PLoS ONE."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1073\/pnas.0707493105","article-title":"MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1","volume":"105","author":"Harris","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B31","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1182\/blood-2012-01-407106","article-title":"AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics","volume":"121","author":"Mocharla","year":"2013","journal-title":"Blood."},{"key":"B32","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.cmet.2019.07.011","article-title":"Extracellular miRNAs: from biomarkers to mediators of physiology and disease","volume":"30","author":"Mori","year":"2019","journal-title":"Cell Metab."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1001\/archneurol.2011.238","article-title":"Natalizumab and impedance of the homing of CD34+ hematopoietic progenitors","volume":"68","author":"Saure","year":"2011","journal-title":"Arch Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"771","DOI":"10.18632\/aging.100693","article-title":"Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells","volume":"6","author":"Olivieri","year":"2014","journal-title":"Aging."},{"key":"B35","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.yjmcc.2012.04.003","article-title":"Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1","volume":"53","author":"Meng","year":"2012","journal-title":"J Mol Cell Car-diol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"45284","DOI":"10.1038\/srep45284","article-title":"MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium","volume":"7","author":"Cerutti","year":"2017","journal-title":"Sci Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/ana.410370111","article-title":"Circulating, soluble adhesion proteins in cerebrospinal fluid and serum of patients with multiple sclerosis: correlation with clinical activity","volume":"37","author":"Dore-Duffy","year":"1995","journal-title":"Ann Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s004150050313","article-title":"Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease","volume":"246","author":"McDonnell","year":"1999","journal-title":"J Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1212\/WNL.48.6.1557","article-title":"Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging","volume":"48","author":"Giovannoni","year":"1997","journal-title":"Neurology."},{"key":"B40","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1001\/archneur.57.4.546","article-title":"Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy","volume":"57","author":"Elovaara","year":"2000","journal-title":"Arch Neurol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"18704","DOI":"10.1073\/pnas.0905063106","article-title":"Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease","volume":"106","author":"Mattes","year":"2009","journal-title":"Proc Natl Acad Sci U S A."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.819911\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T10:05:00Z","timestamp":1646993100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.819911\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,11]]},"references-count":41,"alternative-id":["10.3389\/fneur.2022.819911"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.819911","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,11]]},"article-number":"819911"}}