{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T20:06:04Z","timestamp":1781553964364,"version":"3.54.5"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"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. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Interferon beta (IFN<jats:italic>\u03b2<\/jats:italic>) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFN<jats:italic>\u03b2<\/jats:italic> treatment using an integrated approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN<jats:italic>\u03b2<\/jats:italic>1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4<jats:sup>+<\/jats:sup> T cells and na\u00efve\/memory T cell subsets, by measurement of circulating IFN<jats:italic>\u03b1<\/jats:italic>\/<jats:italic>\u03b2<\/jats:italic> proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping <jats:italic>HLA<\/jats:italic>-<jats:italic>DRB1, -DRB3,4,5, -DQA1<\/jats:italic>, and -<jats:italic>DQB1<\/jats:italic>, using as a control population the <jats:italic>Milieu Interieur<\/jats:italic> cohort of 1,000 French healthy donors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Clinical responders and non-responders displayed similar plasma levels of IFN<jats:italic>\u03b2<\/jats:italic> and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating na\u00efve regulatory T cells, enhanced terminally differentiated effector memory CD4<jats:sup>+<\/jats:sup> T<jats:sub>EMRA<\/jats:sub> cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for <jats:italic>HLA-DQB1<\/jats:italic> genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFN<jats:italic>\u03b2<\/jats:italic>, and in which CD4<jats:sup>+<\/jats:sup> T cells, likely restricted by DQ8 and\/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.628375","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T07:45:22Z","timestamp":1621928722000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon \u03b2 Treatment"],"prefix":"10.3389","volume":"12","author":[{"given":"Priyanka","family":"Devi-Marulkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Moraes-Cabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Campagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9atrice","family":"Corre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Meghraoui-Kheddar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Bondet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Llibre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darragh","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Maillart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Papeix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Pellegrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3871","article-title":"Immunopathology 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