{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:10:56Z","timestamp":1788405056945,"version":"build-2803163510"},"reference-count":82,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["RG#4509A"],"award-info":[{"award-number":["RG#4509A"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"name":"1st Affiliated Hospital of Dalian Medical University","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Joseph Griffin Endowment","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Dysfunctional regulatory T cells and subnormal responses to interferon-\u03b2 disrupt the immune system in multiple sclerosis. We probed dysregulated type I IFN pathways <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> IFN-\u03b2 to induce transcription factors, cytokines, and neurotrophic factors.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>36 MS-relevant serum proteins curated to be relevant to MS were detected with multiplex and IFN activity assays plus western blots of mononuclear cells from 15 partial responders (PR) to IFN-\u03b2 therapy with exacerbations over five years of treatment, and 12 clinical responders (CR) without exacerbations. Response was measured 0, 4, and 24 hours after injection of 16 million units (MU) of IFN-\u03b2 (double-dose) and 8 MU (standard dose), in clinically stable PR and CR, and 16 MU IFN-\u03b2 in paired PR during exacerbations, an IFN-resistant state. IFN-\u03b2 effects after therapy washout were compared to 15 therapy-na\u00efve stable and 13 active RRMS and 18 healthy controls (HC).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>IFN-\u03b2 injection corrected subnormal levels of p-S-STAT1 transcription factor and induced antiviral MxA and type I IFNs. IFN-\u03b2 induced anti-inflammatory IL-4, IL-10, IL-12p40, and TNFRII more strongly in stable PR than CR. Th2 cytokines correlated with serum vitamin D levels in CR. During exacerbations, IFN-\u03b2 injections induced Th1, Th2, and neurotropic proteins. After therapy washout, serum IFN-\u03b1\/\u03b2 and pro-inflammatory IL-12p70 levels were lower in stable CR than in PR. In therapy-na\u00efve MS, Th1, Th2, and neurotrophic protein levels were surprisingly subnormal and poorly intercorrelated. Long-term IFN-\u03b2 therapy elevated serum proteins and brought them to a balanced positively-correlated state, echoing HC.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>IFN-\u03b2 corrects low serum type I IFN levels, enhances responses to subsequent IFN exposure, induces immunoregulatory and neuroprotective proteins, and balances dysregulated and subnormal serum cytokine levels. Low serum IFN and IFN-\u03b2-induced proteins link to better long-term response to IFN-\u03b2 therapy. Correction of immune disruption suggests new mechanisms for immunopathology and therapy.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0330867","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T21:33:20Z","timestamp":1758317600000},"page":"e0330867","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["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"],"prefix":"10.1371","volume":"20","author":[{"given":"Lei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Olcer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9111-8519","authenticated-orcid":true,"given":"Yaerin","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6423-1495","authenticated-orcid":true,"given":"Anthony T.","family":"Reder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"issue":"4","key":"pone.0330867.ref001","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S1474-4422(14)70305-9","article-title":"Role of the innate and adaptive immune responses in the course of multiple sclerosis","volume":"14","author":"B Hemmer","year":"2015","journal-title":"Lancet Neurol"},{"key":"pone.0330867.ref002","first-page":"1","article-title":"Multiple sclerosis: neuroimmunology and pathogenesis.","volume-title":"MedLink Neurology","author":"AT. 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