{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:48:37Z","timestamp":1785408517395,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371821"],"award-info":[{"award-number":["82371821"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271845"],"award-info":[{"award-number":["82271845"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82371821"],"award-info":[{"award-number":["82371821"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82271845"],"award-info":[{"award-number":["82271845"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>B-cell-depleting therapies have revolutionized multiple sclerosis (MS) treatment, yet relapses persist in some patients\u2014suggesting additional pathogenic drivers beyond peripheral B cells. Tertiary lymphoid structures (TLS) are extensively documented in progressive MS at autopsy, but whether their formation begins during the relapsing-remitting phase and how they evolve during the transition to progression remain undefined. Here, using the relapsing-remitting PLP139\u2013151-induced EAE model, we uncover that TLS-like structures form in the subventricular zone during relapse, once established, persist through remission as niches containing both B cells and persistently activated microglia. Neither B-cell depletion alone nor BTK inhibition alone fully prevents relapse. Strikingly, early combined B-cell depletion and BTK inhibition virtually abolishes TLS-like structure formation and may effectively prevent complete disease relapse in this model. By contrast, late initiation of the same combination fails to resolve existing TLS-like structures or prevent relapse, although it attenuates disease severity. These data indicate that established TLS-like structures may represent treatment-resistant compartments, and that both B cells and microglia may be crucial during early formation for sustaining their disease relapse-driving activity. Our study confirms that TLS-like structures may be a key factor driving the compartmentalization of central nervous system inflammation, points to a potentially narrow therapeutic window for intervention, and proposes that early combined B-cell depletion and BTK inhibition may represent a promising strategy worthy of further investigation.<\/jats:p>","DOI":"10.3390\/ijms27125439","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"5439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early Combined B-Cell Depletion and BTK Inhibition Reduced TLS-like Structures and Relapse in PLP139\u2013151-Induced EAE"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5134-1868","authenticated-orcid":false,"given":"Xiujuan","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiurong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hulun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China"},{"name":"The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e210259","DOI":"10.1212\/WNL.0000000000210259","article-title":"Neurodegeneration and Demyelination in the Multiple Sclerosis Spinal Cord: Clinical, Pathological and 7T MRI 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