Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
Journal article, 2023

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

Author

Daniel Jons

University of Gothenburg

Viktor Grut

Umeå University

Tomas Bergström

University of Gothenburg

Sahlgrenska University Hospital

Henrik Zetterberg

University of Gothenburg

Sahlgrenska University Hospital

Martin Biström

Umeå University

Martin Gunnarsson

Faculty of Medicine and Health

M Vrethem

Linköping University

Nicole Brenner

German Cancer Research Center (DKFZ)

Julia Butt

German Cancer Research Center (DKFZ)

Kaj Blennow

University of Gothenburg

Sahlgrenska University Hospital

Staffan Nilsson

University of Gothenburg

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Ingrid Kockum

Karolinska Institutet

Tomas Olsson

Karolinska Institutet

Tim Waterboer

German Cancer Research Center (DKFZ)

Peter Sundström

Umeå University

Oluf Andersen

University of Gothenburg

Journal of Neurology, Neurosurgery and Psychiatry

0022-3050 (ISSN) 1468-330X (eISSN)

Vol. 95 331868

Subject Categories

Neurosciences

Neurology

Cancer and Oncology

DOI

10.1136/jnnp-2023-331868

PubMed

37802637

More information

Latest update

7/17/2024