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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

Authors :
Jons, Daniel
Grut, Viktor
Bergstrom, Tomas
Zetterberg, Henrik
Bistroem, Martin
Gunnarsson, Martin
Vrethem, Magnus
Brenner, Nicole
Butt, Julia
Blennow, Kaj
Nilsson, Staffan
Kockum, Ingrid
Olsson, Tomas
Waterboer, Tim
Sundstrom, Peter
Andersen, Oluf
Jons, Daniel
Grut, Viktor
Bergstrom, Tomas
Zetterberg, Henrik
Bistroem, Martin
Gunnarsson, Martin
Vrethem, Magnus
Brenner, Nicole
Butt, Julia
Blennow, Kaj
Nilsson, Staffan
Kockum, Ingrid
Olsson, Tomas
Waterboer, Tim
Sundstrom, Peter
Andersen, Oluf
Publication Year :
2024

Abstract

BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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.<br />Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

Details

Database :
OAIster
Notes :
application/pdf, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1428119501
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1136.jnnp-2023-331868