MS associated with a broader Epstein-Barr virus specific T-cell receptor repertoire

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 [1]. The second study showed that CSF anti-EBNA1 autoantibodies can cross-react with the CNS autoantigen GliamCAM in a subset of MS patients [2]. “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 [5].

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.

1. Bjornevik K, et al. Science. 2022;375(6578):296–301.
2. Lanz TV, et al. Nature. 2022;603(7900):321–327.
3. 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.
4. Schneider-Hohendorf T, et al. J Exp Med. 2022;219(11):e20220650.
5. Sollid LM. Sci Immunol. 2022;7(70):eabo7799.

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Posted on 20 December 2022