{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T12:43:20Z","timestamp":1792413800642,"version":"4.4.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010255","name":"Aims2Cure","doi-asserted-by":"publisher","award":["HMD00630"],"award-info":[{"award-number":["HMD00630"]}],"id":[{"id":"10.13039\/100010255","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001275","name":"Oak Foundation","doi-asserted-by":"publisher","award":["OFIL-22-254"],"award-info":[{"award-number":["OFIL-22-254"]}],"id":[{"id":"10.13039\/100001275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_00036\/3"],"award-info":[{"award-number":["MC_UU_00036\/3"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031543","name":"Association of British Neurologists","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000627","name":"Guarantors of Brain","doi-asserted-by":"publisher","award":["HMR04540"],"award-info":[{"award-number":["HMR04540"]}],"id":[{"id":"10.13039\/501100000627","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>B-cell-depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalized CNS inflammation, the key pathological driver of disability accrual, remain poorly defined.<\/jats:p>\n                  <jats:p>Here, we leverage anti-CD20 therapy as an in vivo perturbational probe to disentangle MS immunobiology. We combine longitudinal, high-dimensional multimodal immune profiling in patients initiating ocrelizumab with a novel machine learning pipeline to resolve treatment-induced shifts in continuous immune cell states, revealing treatment-associated modulation of shared biological processes that act across the boundaries of discretely partitioned cell types.<\/jats:p>\n                  <jats:p>We identify a distinct chronically activated, proinflammatory\u2013cytotoxic T-cell state with CNS-homing properties that is selectively depleted following B-cell ablation. Importantly, across independent datasets, the same T-cell state is enriched in the circulation of patients with clinically aggressive relapsing disease, in CSF-enriched expanded clonotypes, including a subset with proven Epstein\u2013Barr virus specificity, and in chronically inflamed lesion rims in end-stage MS. Finally, we demonstrate that blockade of lymphocyte trafficking across the blood\u2013brain barrier with the anti-integrin \u03b14 therapy natalizumab leads to enrichment of this cell state in the circulation, demonstrating a mechanistically concordant effect across distinct high-efficacy MS therapies.<\/jats:p>\n                  <jats:p>Together, our findings support a B-cell-dependent pathogenic T-cell state, which links peripheral immune activation to CNS-compartmentalized smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T-cell state might represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.<\/jats:p>","DOI":"10.1093\/brain\/awag303","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:33:26Z","timestamp":1788867206000},"source":"Crossref","is-referenced-by-count":1,"title":["Multimodal discovery of a pathogenic B-cell-dependent T-cell state in multiple sclerosis"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4134-8153","authenticated-orcid":false,"given":"Redwan","family":"Farooq","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0687-1574","authenticated-orcid":false,"given":"Brian","family":"Cutler","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9409-6864","authenticated-orcid":false,"given":"Marco","family":"Pisa","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"Department of Neurology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2771-8261","authenticated-orcid":false,"given":"Subita","family":"Balaram Kuttikkatte","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4779-6133","authenticated-orcid":false,"given":"Jacqueline","family":"Palace","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"Department of Neurology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-5197","authenticated-orcid":false,"given":"Gabriele C","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"Department of Neurology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-3052","authenticated-orcid":false,"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Neurology, St. Josef-Hospital, Ruhr University Bochum , Bochum 44801 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2419-1943","authenticated-orcid":false,"given":"Fabian J","family":"Theis","sequence":"additional","affiliation":[{"name":"Institute of Computational Biology, Helmholtz Munich , Munich 80939 ,","place":["Germany"]},{"name":"TUM School of Life Sciences Weihenstephan, Technical University of Munich , Munich 80333 ,","place":["Germany"]},{"name":"TUM School of Computing, Information and Technology, Technical University of Munich , Munich 80333 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2883-3226","authenticated-orcid":false,"given":"Lars","family":"Fugger","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3387-521X","authenticated-orcid":false,"given":"Kathrine E","family":"Attfield","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DU ,","place":["UK"]},{"name":"MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2026101908012336600_awag303-B1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","article-title":"Multiple 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