{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:15:29Z","timestamp":1785417329154,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006692","name":"University of Turin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/048tbm396","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroinflammation in multiple sclerosis (MS) is driven by the infiltration of myelin-reactive T cells into the central nervous system (CNS). Interferon-\u03b2 (IFN-\u03b2) is one of the earliest disease-modifying treatments (DMTs) approved for MS and remains widely used in special populations (pregnant and elderly patients) owing to its favorable safety profile. However, the exact mechanism of action of this drug and reliable biomarkers of treatment response remain unclear. Transcriptomic profiling and data integration approaches offer powerful tools for investigating complex patterns of regulation and molecular mechanisms underlying therapeutic efficacy. In this study, we performed an integrative analysis of openly available transcriptomic datasets to characterize IFN-\u03b2-induced gene expression changes in MS patients. By combining data from large independent cohorts, we identified a 43-gene transcriptional signature consistently associated with IFN-\u03b2 treatment across disease stages, including progressive MS. To explore the relevance of this signature, we cross-referenced the 43-gene signature with publicly available expression quantitative trait loci (eQTL) datasets to determine whether these genes could be influenced by known MS-associated risk variants highlighting Interferon-Induced Transmembrane Protein 3 (IFITM3) as a candidate molecular mediator of MS. This integrative approach provides new insights into IFN-\u03b2-driven immune modulation and supports the development of therapeutic strategies for MS.<\/jats:p>","DOI":"10.3390\/ijms27125329","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"5329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Transcriptomics Uncovers IFN-\u03b2 Signature and IFITM3 as Putative Molecular Mediator in MS"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7153-2248","authenticated-orcid":false,"given":"Alessandro","family":"Maglione","sequence":"first","affiliation":[{"name":"Department of Computer Science, University of Turin, 10124 Torino, Italy"},{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-3388","authenticated-orcid":false,"given":"Rachele","family":"Rosso","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6371-7354","authenticated-orcid":false,"given":"Simona","family":"Rolla","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0045-3806","authenticated-orcid":false,"given":"Eleonora","family":"Virgilio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"},{"name":"Neurology Unit, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinella","family":"Clerico","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"},{"name":"Neurology Unit, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Makarevi\u010dius, G., Kizlaitien\u0117, R., Kaubrys, G., and Giedraitien\u0117, N. (2025). Predictors of therapy switching to high-efficacy disease-modifying therapies in patients with multiple sclerosis: A single center, retrospective, observational study. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1635618"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Arnold, D.L., Calabresi, P.A., Kieseier, B.C., Sheikh, S.I., Deykin, A., Zhu, Y., Liu, S., You, X., Sperling, B., and Hung, S. (2014). Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: Results from a randomized controlled trial in relapsing-remitting multiple sclerosis. BMC Neurol., 14.","DOI":"10.1186\/s12883-014-0240-x"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1001\/jama.2020.26858","article-title":"Diagnosis and Treatment of Multiple Sclerosis: A Review","volume":"325","author":"McGinley","year":"2021","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1177\/13524585241308134","article-title":"Recommendations for essential medicines for multiple sclerosis in low-resource settings","volume":"31","author":"Saylor","year":"2025","journal-title":"Mult. Scler."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1007\/s00415-020-09762-y","article-title":"Pregnancy outcomes in interferon-beta-exposed patients with multiple sclerosis: Results from the European Interferon-beta Pregnancy Registry","volume":"267","author":"Hellwig","year":"2020","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Capasso, N., Virgilio, E., Covelli, A., Giovannini, B., Foschi, M., Montini, F., Nasello, M., Nilo, A., Prestipino, E., and Schir\u00f2, G. (2023). Aging in multiple sclerosis: From childhood to old age, etiopathogenesis, and unmet needs: A narrative review. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1207617"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e001108","DOI":"10.1136\/bmjno-2025-001108","article-title":"Real-world use of disease-modifying therapy in persons with multiple sclerosis aged 55 and over","volume":"7","author":"Salmen","year":"2025","journal-title":"BMJ Neurol. Open"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00760","DOI":"10.1016\/j.neurot.2025.e00760","article-title":"Prevalence of hypogammaglobulinemia after non-anti-CD20 therapies and impact of switching to rituximab\/ocrelizumab in multiple sclerosis","volume":"22","author":"Perriguey","year":"2025","journal-title":"Neurotherapeutics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1177\/13524585251368687","article-title":"Prevalence of multiple sclerosis and disease-modifying therapy use in older adults in the United States, 2011\u20132021","volume":"31","author":"Li","year":"2025","journal-title":"Mult. Scler. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6939","DOI":"10.2147\/JMDH.S527886","article-title":"A Review of the Impact of Platform Therapies (DMTs) on Associated Clinical Symptoms of Multiple Sclerosis","volume":"18","author":"Shirol","year":"2025","journal-title":"J. Multidiscip. Healthc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/S1474-4422(23)00154-0","article-title":"Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): A multicentre, randomised, single-blind, phase 4, non-inferiority trial","volume":"22","author":"Corboy","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1007\/s12035-021-02454-2","article-title":"Pharmacogenetic Predictors of Response to Interferon Beta Therapy in Multiple Sclerosis","volume":"58","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a032003","DOI":"10.1101\/cshperspect.a032003","article-title":"Interferon \u03b2 for Multiple Sclerosis","volume":"8","author":"Jakimovski","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1002\/glia.23172","article-title":"Interferon-\u03b2 regulates the production of IL-10 by toll-like receptor-activated microglia","volume":"65","author":"Carriche","year":"2017","journal-title":"Glia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3672353","DOI":"10.1155\/2016\/3672353","article-title":"Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients","volume":"2016","author":"Trentini","year":"2016","journal-title":"Dis. Markers"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.msard.2016.12.003","article-title":"Multiple sclerosis: Association of gelatinase B\/matrix metalloproteinase-9 with risk and clinical course the disease","volume":"11","author":"Valado","year":"2017","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/icb.2016.55","article-title":"Interferon-\u03b2 therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis","volume":"94","author":"Rizzo","year":"2016","journal-title":"Immunol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/ana.21652","article-title":"T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta","volume":"65","author":"Durelli","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s00415-017-8625-6","article-title":"Blood lymphocyte subsets identify optimal responders to IFN-beta in MS","volume":"265","author":"Alenda","year":"2018","journal-title":"J. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2332340","DOI":"10.1080\/08916934.2024.2332340","article-title":"Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis","volume":"57","author":"Xue","year":"2024","journal-title":"Autoimmunity"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hurtado-Guerrero, I., Pinto-Medel, M.J., Urbaneja, P., Rodriguez-Bada, J.L., Le\u00f3n, A., Guerrero, M., Fern\u00e1ndez, \u00d3., Leyva, L., and Oliver-Martos, B. (2017). Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFN\u00df in Multiple Sclerosis Patients According to the Therapeutic Response to IFN\u00df. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170031"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Devi-Marulkar, P., Moraes-Cabe, C., Campagne, P., Corre, B., Meghraoui-Kheddar, A., Bondet, V., Llibre, A., Duffy, D., Maillart, E., and Papeix, C. (2021). Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon \u03b2 Treatment. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.628375"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110339","DOI":"10.1016\/j.clim.2024.110339","article-title":"Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity","volume":"267","author":"Coelewij","year":"2024","journal-title":"Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Malhotra, S., Bustamante, M.F., P\u00e9rez-Miralles, F., Rio, J., Ruiz de Villa, M.C., Vegas, E., Nonell, L., Deisenhammer, F., Fissolo, N., and Nurtdinov, R.N. (2011). Search for specific biomarkers of IFN\u03b2 bioactivity in patients with multiple sclerosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023634"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"153ra131","DOI":"10.1126\/scitranslmed.3004186","article-title":"An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity","volume":"4","author":"Ottoboni","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4194","DOI":"10.1093\/hmg\/ddt267","article-title":"Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls","volume":"22","author":"Nickles","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jns.2011.09.032","article-title":"Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis","volume":"313","author":"Feng","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/s41467-020-16625-7","article-title":"Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica","volume":"11","author":"Agasing","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e337","DOI":"10.1212\/NXI.0000000000000337","article-title":"Dysregulation of MS risk genes and pathways at distinct stages of disease","volume":"4","author":"Srinivasan","year":"2017","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nri3787","article-title":"Type I interferons in infectious disease","volume":"15","author":"McNab","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jangra, S., Yuen, K.S., Botelho, M.G., and Jin, D.Y. (2019). Epstein-Barr Virus and Innate Immunity: Friends or Foes?. Microorganisms, 7.","DOI":"10.3390\/microorganisms7060183"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1126\/science.abj8222","article-title":"Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis","volume":"375","author":"Bjornevik","year":"2022","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gurevich, M., Miron, G., Falb, R.Z., Magalashvili, D., Dolev, M., Stern, Y., and Achiron, A. (2015). Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis. BMC Neurol., 15.","DOI":"10.1186\/s12883-015-0495-x"},{"key":"ref_34","unstructured":"International Multiple Sclerosis Genetics Consortium (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science, 365, eaav7188."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"gkaf207","DOI":"10.1093\/nar\/gkaf207","article-title":"An evolutionarily conserved constellation of functional cis-elements programs the virus-responsive fate of the human (epi)genome","volume":"53","author":"Koutsi","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"841","DOI":"10.17219\/acem\/121063","article-title":"A long-term follow-up study on biochemical and clinical biomarkers of response to interferon beta-1b treatment in relapsing-remitting multiple sclerosis","volume":"29","author":"Pietrzak","year":"2020","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Li, L., Olcer, M., Wang, Z., Song, Y., Ke, J., Feng, X., and Reder, A.T. (2025). IFN-\u03b2 therapy rescues dysregulated IFN-stimulated proteins, serum cytokines, and neurotrophic factors in multiple sclerosis: Multiplex analysis of short-term and long-term IFN responses. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0330867"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.cytogfr.2014.12.002","article-title":"Biological monitoring of IFN-\u03b2 therapy in Multiple Sclerosis","volume":"26","author":"Bertolotto","year":"2015","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1111\/j.1468-1331.2009.02716.x","article-title":"Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation","volume":"16","author":"Sellebjerg","year":"2009","journal-title":"Eur. J. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1191\/135248506ms1245oa","article-title":"Biological markers of interferon-beta therapy: Comparison among interferon-stimulated genes MxA, TRAIL and XAF-1","volume":"12","author":"Gilli","year":"2006","journal-title":"Mult. Scler. J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Karathanasis, D.K., Rapti, A., Nezos, A., Skarlis, C., Kilidireas, C., Mavragani, C.P., and Evangelopoulos, M.E. (2022). Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.898049"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ko\u0161\u0107ak Luka\u010d, J., Baronica, K.B., \u0160u\u0107ur, A., Sremec, J., Tomasovi\u0107, S., Baronica, R., Kelava, T., Gr\u010devi\u0107, D., and Kova\u010di\u0107, N. (2024). Serum Concentrations of Chemokines CCL20, CXCL8 and CXCL10 in Relapsing-Remitting Multiple Sclerosis and Their Association with Presence of Antibodies against Epstein-Barr Virus. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158064"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jneuroim.2016.01.010","article-title":"A gene expression study denies the ability of 25 candidate biomarkers to predict the interferon-beta treatment response in multiple sclerosis patients","volume":"292","author":"Martire","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5633","DOI":"10.1038\/s41598-018-24032-8","article-title":"Integrative analysis of Multiple Sclerosis using a systems biology approach","volume":"8","author":"Husi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111501","DOI":"10.1016\/j.intimp.2024.111501","article-title":"Knockdown of IFIT3 ameliorates multiple sclerosis via selectively regulating M1 polarization of microglia in an experimental autoimmune encephalomyelitis model","volume":"128","author":"Sun","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.isci.2018.12.020","article-title":"Quantitative Proteomics Reveals the Dynamic Protein Landscape during Initiation of Human Th17 Cell Polarization","volume":"11","author":"Tripathi","year":"2019","journal-title":"iScience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e0334724","DOI":"10.1128\/mbio.03347-24","article-title":"IFITM3 variants point to a critical role in emergent virus infections","volume":"16","author":"Denz","year":"2025","journal-title":"mBio"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"155957","DOI":"10.1016\/j.cyto.2022.155957","article-title":"Impact of interferon-induced transmembrane protein 3 gene rs12252 polymorphism on COVID-19 mortality","volume":"157","author":"Ahmadi","year":"2022","journal-title":"Cytokine"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1089\/omi.2022.0023","article-title":"Multiple Sclerosis Biomarker Candidates Revealed by Cell-Type-Specific Interactome Analysis","volume":"26","author":"Yurduseven","year":"2022","journal-title":"Omics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"103656","DOI":"10.1016\/j.mcn.2021.103656","article-title":"An integrative study of genetic variants with brain tissue expression identifies viral etiology and potential drug targets of multiple sclerosis","volume":"115","author":"Manuel","year":"2021","journal-title":"Mol. Cell. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5329\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:11:00Z","timestamp":1781842260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125329"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125329","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]}}}