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Peer-reviewedCC BY 4.0Frontiers in Immunology

High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis

  • Stephan Neidhart1,2,3
  • Klara Asplund Högelin4,5
  • Marc Hilty1,2,3
  • Benjamin Vlad1,6
  • Mario Ziegler1
  • Mohsen Khademi4
  • Andreas Lutterotti1,2,3,7
  • Roland Martin1,7,8,9
  • Faiez Al Nimer4
  • Ilijas Jelcic1,2,3
9 affiliations
  1. 1Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich
  2. 2Department of Neurology, Hirslanden Klinik Zurich
  3. 3Center for Multiple Sclerosis and Clinical Neuroimmunology, Bellevue Medical Group
  4. 4Neuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet
  5. 5Department of Laboratory Medicine, Karolinska Institutet
  6. 6Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital
  7. 7Cellerys AG
  8. 8Institute of Experimental Immunology, University of Zurich
  9. 9Therapeutic Immune Design Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet
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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.

Methods: 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.

Results: 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.

Conclusion: 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.

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Cite

BibTeXRIS
BibTeX
@article{neidhart2026high,
  title = {{High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis}},
  author = {Stephan Neidhart and Klara Asplund Högelin and Marc Hilty and Benjamin Vlad and Mario Ziegler and Mohsen Khademi and Andreas Lutterotti and Roland Martin and Faiez Al Nimer and Ilijas Jelcic},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1929166},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1929166/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - High EBV-reactive IgG levels in serum are linked to typical inflammatory cerebrospinal fluid features in multiple sclerosis
AU  - Stephan Neidhart
AU  - Klara Asplund Högelin
AU  - Marc Hilty
AU  - Benjamin Vlad
AU  - Mario Ziegler
AU  - Mohsen Khademi
AU  - Andreas Lutterotti
AU  - Roland Martin
AU  - Faiez Al Nimer
AU  - Ilijas Jelcic
PY  - 2026
DA  - 2026/10/05
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1929166
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1929166/full
AB  - 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.  Methods: 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.  Results: 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.  Conclusion: 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.
SN  - 1664-3224
ER  -