{ "abstract": "Background: 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.\n\nMethods: 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 hi ) 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) ≥1.5. 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–response analyses.\n\nResults: sEBNA1-IgG hi levels were associated with higher CSF leukocyte counts (median 6.0 vs 3.0 cells/µL; 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 hi 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 (β=0.405, 95% CI 0.217–0.592, p=2.86×10 –5 ) and 2.73-fold higher odds for pleocytosis (OR = 2.73, 95% CI 1.59–4.71, p=2.83×10 –4 ), 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\nConclusion: 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 hi - than sEBV-CA-IgG hi -reactivity links to general intrathecal cellular and humoral immune activation in MS.", "abstract_shown": true, "affiliations": [ "Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich", "Department of Neurology, Hirslanden Klinik Zurich", "Center for Multiple Sclerosis and Clinical Neuroimmunology, Bellevue Medical Group", "Neuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet", "Department of Laboratory Medicine, Karolinska Institutet", "Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital", "Cellerys AG", "Institute of Experimental Immunology, University of Zurich", "Therapeutic Immune Design Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet" ], "article_type": "research support, non u.s. gov't", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Stephan Neidhart" }, { "affs": [ 3, 4 ], "name": "Klara Asplund Högelin" }, { "affs": [ 0, 1, 2 ], "name": "Marc Hilty" }, { "affs": [ 0, 5 ], "name": "Benjamin Vlad" }, { "affs": [ 0 ], "name": "Mario Ziegler" }, { "affs": [ 3 ], "name": "Mohsen Khademi" }, { "affs": [ 0, 1, 2, 6 ], "name": "Andreas Lutterotti" }, { "affs": [ 0, 6, 7, 8 ], "name": "Roland Martin" }, { "affs": [ 3 ], "name": "Faiez Al Nimer" }, { "affs": [ 0, 1, 2 ], "name": "Ilijas Jelcic" } ], "bibtex": "https://research.draconitic.com/paper/4x4dnwm86me2j.bib", "cited_by": 0, "doi": "10.3389/fimmu.2026.1929166", "fulltext_url": "https://europepmc.org/articles/PMC13677834", "id": "4x4dnwm86me2j", "issns": [ "1664-3224" ], "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1929166/full", "language": "eng", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2734|Multiple Sclerosis Research Studies" ] ], "openalex": "W7220441384", "pdf_url": "https://europepmc.org/articles/PMC13677834?pdf=render", "pmcid": "PMC13677834", "pmid": "42898310", "published": "2026-10-05", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/4x4dnwm86me2j.ris", "sources": [ { "first_seen": "2026-10-30T12:19:15Z", "native_id": "10.3389/fimmu.2026.1929166", "source": "crossref", "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1929166/full" }, { "first_seen": "2026-10-30T12:19:37Z", "native_id": "MED:42898310", "source": "europepmc", "url": "https://europepmc.org/article/MED/42898310" } ], "subjects": [ { "field": "biology", "origin": "issn:1664-3224", "subfield": "immunology" } ], "title": "High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis", "title_text": "High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:37Z", "url": "https://research.draconitic.com/paper/4x4dnwm86me2j", "venue": "Frontiers in Immunology", "versions": [] }