{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:18:28Z","timestamp":1787894308096,"version":"build-2784847793"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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":"\n Introduction<\/jats:title>\n \n Multiple sclerosis (MS) is associated with compartmentalized B-cell responses in the cerebrospinal fluid (CSF), where CXCR3\n +<\/jats:sup>\n B cells contribute to intrathecal immune activity and tissue injury. Zinc is an important regulator of immune-cell function, but zinc homeostasis in pathogenic B-cell populations in MS remains poorly defined.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We reanalyzed two publicly available human single-cell RNA sequencing datasets containing CSF and peripheral blood (PB) B cells from healthy or non-MS controls and patients with clinically isolated syndrome or MS. Zinc transporter and metallothionein (Zn\/MT) gene expression was examined in CXCR3\n +<\/jats:sup>\n and CXCR3\n \u2212<\/jats:sup>\n B-cell subsets, and a composite Zn\/MT signature was calculated at the patient level.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A composite Zn\/MT signature was significantly elevated in MS relative to controls in both PB and CSF, and in both CXCR3\n +<\/jats:sup>\n and CXCR3\n \u2212<\/jats:sup>\n B cells, indicating a disease-associated feature of B cells broadly rather than one restricted to CXCR3\n +<\/jats:sup>\n cells. In CSF CXCR3\n +<\/jats:sup>\n B cells, this increase was driven by several zinc transporters, including\n SLC39A11<\/jats:italic>\n (ZIP11),\n SLC30A9<\/jats:italic>\n (ZnT9), and\n SLC39A6<\/jats:italic>\n (ZIP6), whereas no individual gene reached significance in PB. Direct comparison of CXCR3\n +<\/jats:sup>\n and CXCR3\n \u2212<\/jats:sup>\n B cells revealed a disease-specific divergence in PB, with a significantly higher Zn\/MT signature in CXCR3\n +<\/jats:sup>\n cells from MS patients but not healthy controls. Five genes contributed to this effect.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n These findings identify altered zinc-homeostasis pathways as a disease-associated feature of B cells in MS and reveal a disease-specific divergence between CXCR3\n +<\/jats:sup>\n and CXCR3\n \u2212<\/jats:sup>\n B-cell subsets in peripheral blood. The results support further investigation of zinc-regulatory mechanisms in B cell-mediated neuroinflammation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1922905","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:34:43Z","timestamp":1787891683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Zinc and metallothionein dysregulation in B cells in multiple sclerosis, with disease-specific CXCR3+\/CXCR3\u207b divergence in blood"],"prefix":"10.3389","volume":"17","author":[{"given":"Remi","family":"Fritzen","sequence":"first","affiliation":[{"name":"School of Physics and Astronomy, University of St Andrews","place":["St Andrews, United Kingdom"]},{"name":"Centre of Biophotonics, University of St Andrews","place":["St Andrews, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2020.05.049","article-title":"Treatment of multiple sclerosis: a review","volume":"133","author":"Hauser","year":"2020","journal-title":"Am J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.04.066","article-title":"How do immune cells overcome the blood-brain barrier in multiple sclerosis","volume":"585","author":"Larochelle","year":"2011","journal-title":"FEBS Lett"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2008523117","article-title":"A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis","volume":"117","author":"Ramesh","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25508","article-title":"Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis","volume":"86","author":"van Langelaar","year":"2019","journal-title":"Ann Neurol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2024.02.013","article-title":"Twin study dissects CXCR3(+) memory B cells as non-heritable feature in multiple sclerosis","volume":"5","author":"Ingelfinger","year":"2024","journal-title":"Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102027","article-title":"T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis","volume":"6","author":"Jelcic","year":"2025","journal-title":"Cell Rep Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.3390\/biom13081204","article-title":"CXCL10 is associated with increased cerebrospinal fluid immune cell infiltration and disease duration in multiple sclerosis","volume":"13","author":"Blandford","year":"2023","journal-title":"Biomolecules"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/68.2.447s","article-title":"Zinc and immune function: the biological basis of altered resistance to infection","volume":"68","author":"Shankar","year":"1998","journal-title":"Am J Clin Nutr"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2018.11.008","article-title":"Variation in trace element content between liver lobes in cattle. 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