You are here

  • Home
  • Archive
  • Volume 95, Issue 4
  • Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage

Article Text

Article menu
Multiple sclerosis
Original research
Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
  1. Daniel Jons1,
  2. Viktor Grut2,
  3. Tomas Bergström3,4,
  4. Henrik Zetterberg5,6,
  5. Martin Biström2,
  6. Martin Gunnarsson7,
  7. Magnus Vrethem8,
  8. Nicole Brenner9,
  9. Julia Butt9,
  10. Kaj Blennow5,6,
  11. Staffan Nilsson10,11,
  12. Ingrid Kockum12,
  13. Tomas Olsson12,
  14. Tim Waterboer9,
  15. Peter Sundström2,
  16. Oluf Andersen1
  1. 1 Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
  2. 2 Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden
  3. 3 Department of Infectious Diseases, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
  4. 4 Department of Clinical Microbiology, Sahlgrenska University Hospital, Göteborg, Sweden
  5. 5 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
  6. 6 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  7. 7 Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
  8. 8 Department of Neurology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
  9. 9 Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center, Heidelberg, Germany
  10. 10 Mathematical Sciences, Chalmers University of Technology, Göteborg, Sweden
  11. 11 Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden
  12. 12 Department of Clinical Neuroscience, The Karolinska Neuroimmunology & Multiple Sclerosis Center, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
  1. Correspondence to Dr Daniel Jons, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden; daniel.jons{at}vgregion.se; Professor Oluf Andersen; oluf.andersen{at}neuro.gu.se

Abstract

Background Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens.

Methods We performed a case–control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury.

Results EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15–20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001–0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10−5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026).

Conclusions Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

  • MULTIPLE SCLEROSIS
  • VIROLOGY

Data availability statement

Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, DJ, on reasonable request.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jnnp-2023-331868

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Data availability statement

    Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, DJ, on reasonable request.

    View Full Text

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors DJ is the guarantor of the study and accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish. DJ, PS and OFA contributed to the conception and design of the study; all authors contributed to the acquisition and analysis of data; DJ, SN, PS and OFA contributed to drafting the text and preparing the figures. SN and DJ performed the statistical analysis. All authors discussed the results, contributed to, and approved the final manuscript.

    • Funding DJ was supported by grants from the Swedish State under the ALF agreement between the Swedish Government and County Councils (ALFGBG-772071), as well as by grants from the Research Foundation of the Gothenburg MS Society, Bjornsson Research Foundation, Gothenburg, Sweden, and The Gothenburg Society of Medicine. VG was supported by the Visare Norr Fund, Northern County Councils’ Regional Federation, the Research and Development Unit, Region Jämtland Härjedalen, the Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden, Oskarfonden, and NEURO Sweden. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation—USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21- 831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden—Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at University College London (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation—USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the US National Institutes of Health (grant EBV before MS-induced neuronal damage #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21- 848495). TO has received grants from the Swedish Research Council, the Swedish Brain Foundation, Knut and Alice Wallenberg Foundation, and Margaretha af Ugglas Foundation. IK was supported by a European Horizon 2020 grant (MultipleMS, project nr 733161), the Swedish Research Foundation (grant no. 2020-01638), and the Swedish Brain Foundation.

    • Competing interests HZ has served on scientific advisory boards and/or as a consultant for AbbVie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, NervGen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, AlzeCure, Biogen and Roche; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is part of the GU Ventures Incubator Program, outside the work presented in this paper. TO has received advisory board/lecture honoraria from Biogen, Novartis, Merck, and Sanofi. The same companies have provided unrestricted MS research grants. MB has received a speaker fee from Biogen. PS will serve as an unpaid consultant for Moderna. KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and also is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.