{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:54:00Z","timestamp":1791179640629,"version":"4.1.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["O2021-0283"],"award-info":[{"award-number":["O2021-0283"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Epstein-Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). However, it is ill-defined which of the MS-typical inflammatory alterations of basic cerebrospinal fluid (CSF) parameters, i.e. intrathecal cellular inflammation versus intrathecal total production of antibodies, are primarily linked to EBV-mediated humoral immune signatures in serum and\/or CSF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed paired serum and cerebrospinal fluid (CSF) samples from 316 MS patients from Switzerland and Sweden. Serum IgG levels (sIgG) against EBV nuclear antigen 1 (EBNA1) and EBV capsid antigen (EBV-CA) were quantified by ELISA, and high levels (IgG\n                      <jats:sup>hi<\/jats:sup>\n                      ) were defined as the highest quartile (Q4) of serum EBNA1- or EBV-CA-specific IgG levels (sEBNA1-IgG or sEBV-CA-IgG), respectively. Intrathecal EBV-specific antibody production was defined as CSF\/serum antigen-specific antibody index (CAI) \u22651.5. We assessed associations of EBV-specific measures with CSF leukocyte count, presence of pleocytosis, presence of blood-CSF barrier dysfunction, presence of CSF-specific oligoclonal bands (OCB) and intrathecal immunoglobulin indices\/fractions using correction for multiple comparisons, as well as age- and sex-adjusted models and continuous dose\u2013response analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      sEBNA1-IgG\n                      <jats:sup>hi<\/jats:sup>\n                      levels were associated with higher CSF leukocyte counts (median 6.0 vs 3.0 cells\/\u00b5L; q=0.022), more frequent pleocytosis (55.7% vs 37.6%; q=0.022), and higher rate of CSF-specific OCB (93.7% vs 79.3%; q=0.029) compared to lower sEBNA1-IgG levels. sEBV-CA-IgG\n                      <jats:sup>hi<\/jats:sup>\n                      levels were not associated with cellular CSF parameters, but with a higher total IgG index (0.78 vs 0.65; q=0.016). In age- and sex-adjusted models, a 10-fold increase in sEBNA1-IgG levels was associated with a 2.54-fold higher CSF leukocyte count (\u03b2=0.405, 95% CI 0.217\u20130.592, p=2.86\u00d710\n                      <jats:sup>\u20135<\/jats:sup>\n                      ) and 2.73-fold higher odds for pleocytosis (OR\u00a0=\u00a02.73, 95% CI 1.59\u20134.71, p=2.83\u00d710\n                      <jats:sup>\u20134<\/jats:sup>\n                      ), whereas sEBV-CA-IgG showed no significant correlation. Dose-response models showed monotonic associations between sEBNA1-IgG levels and both CSF leukocyte counts and general intrathecal humoral activation, whereas sEBV-CA-IgG levels were associated mainly with overall intrathecal humoral activity. Intrathecal EBV-specific antibody production was uncommon and not associated with basic CSF inflammatory or barrier parameters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings are consistent with an outside-in model, in which peripheral, but not intrathecal activation of EBV-specific humoral immunity, and rather sEBNA1-IgG\n                      <jats:sup>hi<\/jats:sup>\n                      - than sEBV-CA-IgG\n                      <jats:sup>hi<\/jats:sup>\n                      -reactivity links to general intrathecal cellular and humoral immune activation in MS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1929166","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:32:28Z","timestamp":1791178348000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Stephan","family":"Neidhart","sequence":"first","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich","place":["Zurich, Switzerland"]},{"name":"Department of Neurology, Hirslanden Klinik Zurich","place":["Zurich, Switzerland"]},{"name":"Center for Multiple Sclerosis and Clinical Neuroimmunology, Bellevue Medical Group","place":["Zurich, 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Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Vlad","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich","place":["Zurich, Switzerland"]},{"name":"Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital","place":["Jena, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Khademi","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska 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