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Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Clinical Microbiology, Sahlgrenska University Hospital, Göteborg, Sweden.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
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2024 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 95, no 4, p. 325-332Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2024. Vol. 95, no 4, p. 325-332
Keywords [en]
MULTIPLE SCLEROSIS, VIROLOGY
National Category
Neurology
Identifiers
URN: urn:nbn:se:oru:diva-108881DOI: 10.1136/jnnp-2023-331868ISI: 001085444600001PubMedID: 37802637Scopus ID: 2-s2.0-85174051593OAI: oai:DiVA.org:oru-108881DiVA, id: diva2:1803996
Funder
Region Jämtland HärjedalenSwedish Research Council, 2018-02532 2017-00915 2020-01638Stiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228 FO2017- 0243EU, Horizon 2020, 860197 733161Alzheimerfonden, 742881Knut and Alice Wallenberg Foundation
Note

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 Jaemtland Haerjedalen, 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 foer Gamla Tjaenarinnor, Hjaernfonden-Sweden (#FO2019- 0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska- 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.

Available from: 2023-10-11 Created: 2023-10-11 Last updated: 2024-04-11Bibliographically approved

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