New research data suggest that MS may be preceded by Epstein-Barr virus (EBV) infection but may be also associated with a broader EBV-specific T-cell receptor (TCR) repertoire. This is consistent with the assumption that there is an ongoing aberrant immune response to EBV in MS patients. Alternatively, it could be the remnant of a disease-triggering event or an ongoing CD8+ immune response to EBV.
2022 has seen renewed interest in the possible relationship between EBV and MS, with the publication of 2 very important studies. One showed, in a large cohort, that EBV seroconversion precedes MS by years and that CNS damage measured by neurofilament light (NfL) is detectable after EBV seroconversion . The second study showed that CSF anti-EBNA1 autoantibodies can cross-react with the CNS autoantigen GliamCAM in a subset of MS patients . “It is tempting to assume that EBV infection could trigger the autoimmune process behind MS,” said Dr Tilman Schneider-Hohendorf (University of Muenster, Germany) [3,4]. Other evidence implicates EBV as a driver rather than a trigger for MS, in which case elimination of EBV would be a rational therapy for MS .
To further clarify the role of EBV in MS, Dr Schneider-Hohendorf and colleagues studied the CD8+, EBV-specific T-cell receptor beta chain (TRBV) repertoire in 3 independent cohorts: 1,396 MS patients and 229 controls (discovery cohort); 59 MS patients and 51 controls (validation cohort); and 35 monozygotic, MS-discordant twin pairs (monozygotic twin cohort). Also retrieved were multimer-binding TRBV sequences from public databases specific to 4 pathogens: EBV-cytomegalovirus, influenza A, and SARS-CoV-2. Pathogen-specific TRBV sequences were quantified in peripheral blood.
The results showed a higher number of unique, EBV-specific, MHC-I restricted CD8+ T-cell sequences in MS patients. This finding was consistent in all 3 cohorts, thus excluding genetic as well as early environmental factors. “What we see here, is very likely an imprint of an aberrant primary response to EBV,” said Dr Schneider-Hohendorf. “However, it could also be an ongoing EBV response.” Anti-VLA4 therapy (natalizumab) resulted in a preferential increase in EBV-specific TRBV sequences. But as all the studied pathogenic cells should be blocked equally, the authors rather speculated their observations to be consistent with continuous EBV response causing continuous egress of EBV-specific clonotypes from blood to tissue, which then accumulate and are made visible by the treatment. Based on single-cell RNA sequencing of CSF, a sign of increased, EBV-associated CD8+ T-cell CNS immune surveillance was seen in MS, which can lead to ongoing CD8+ lytic EBV-specific response.
- Bjornevik K, et al. Science. 2022;375(6578):296–301.
- Lanz TV, et al. Nature. 2022;603(7900):321–327.
- Schneider-Hohendorf T, et al. Broader Epstein-Barr virus-specific T-cell receptor repertoire in patients with multiple sclerosis. Abstract O182, ECTRIMS 2022, 26–28 October, Amsterdam, the Netherlands.
- Schneider-Hohendorf T, et al. J Exp Med. 2022;219(11):e20220650.
- Sollid LM. Sci Immunol. 2022;7(70):eabo7799.
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Table of Contents: ECTRIMS 2022
Letter from the Editor
ECTRIMS 2022 Highlights Podcast
Diagnosis and Prediction of Disease Course
A case for including optic nerve lesions in the McDonald criteria
Cerebrospinal fluid kappa-free light chains for MS diagnosis
Early, non-disabling relapses increase disability accumulation
Physical impairment is present before perceived MS onset
Chronic active MS lesions respond poorly to anti-CD20 antibodies
Treatment: Trials & Strategies
Dimethyl fumarate reduces the risk of a first clinical event in RIS
How and when to make a timely switch to high-efficacy DMT
Comparing real-world effectiveness of DMTs
Study fails to show non-inferiority of rituximab to ocrelizumab
Autologous haematopoietic stem cell transplantation versus DMTs
Stem cell transplantation not superior to natalizumab in progressive MS
Efficacy of DMTs fades away in secondary progressive MS
Smartphone tapping can help detect progressive MS
Early treatment with DMT effective in paediatric-onset MS
Fingolimod in paediatric MS: results of up to 6 years
Switching treatment after initial platform injectable DMT: real-world data
Pregnancy and infant outcomes in women receiving ocrelizumab
New safety data of anti-CD20 mAbs around pregnancy
MS activity and pregnancy outcomes after long-term use of natalizumab
Ravulizumab significantly reduced relapses in AQP4+ NMOSD
NMOSD patients are cognitively impaired regardless of serostatus
Evidence-based consensus on pregnancy in NMOSD
COVID-19 and MS: lessons learned thus far
Ocrelizumab and fingolimod increase the risk of COVID-19 and of worse outcomes
Humoral and cellular immune responses after SARS-CoV-2 vaccination
Re-myelination strategies in MS still pose many unanswered questions
MS associated with a broader Epstein-Barr virus specific T-cell receptor repertoire
Cognitive rehab and mindfulness reduce cognitive complaints in MS
Sustained reduction in disability progression with ocrelizumab
Ublituximab meets primary endpoint for relapsing MS
Clinical relevance of neurofilament light chain levels