New research suggests that not only is MS preceded by Epstein-Barr virus (EBV) infection, but it is 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.

In 2022, there was 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 other one 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 EBV infection could trigger the autoimmune process behind MS,” Dr. Tilman Schneider-Hohendorf said (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 investigated the peripheral blood CD8, EBV-specific T-cell receptor beta chain (TRBV) repertoire of 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). They also retrieved multimer-binding TRBV sequences from public databases specific to 4 pathogens: EBV-CMV, influenza A, and SARS-CoV-2. Pathogen-specific TRB sequences were quantified in peripheral blood TCBV.

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, however, it could also be an ongoing EBV response,” said Dr Schneider-Hohendorf. Anti-VLA4 therapy (natalizumab) resulted in a preferential increase in EBV-specific TRBV sequences. The authors speculate, however, that this is consistent with continuous EBV response causing continuous egress of EBV-specific clonotypes from blood to tissue, which then accumulates 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.

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