A recent cross-sectional study has identified a distinct immune response to the Epstein-Barr virus (EBV) in patients with multiple sclerosis (MS) compared to those with other demyelinating disorders. The findings, presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress and published in Brain, suggest that this unique response may play a role in the pathogenesis of MS and could be modulated by certain MS treatments.
The study, led by Tilman Schneider-Hohendorf, PhD, from Münster University Hospital in Germany, analyzed 1317 peripheral blood T-cell receptor β chain (TRB) repertoire samples from healthy donors (n = 409), MS patients (n = 710), and patients with NMOSD (n = 87), MOGAD (n = 64), and Susac’s Syndrome (n = 47). Researchers looked for the presence of unique EBV-specific TRB sequences. The results showed that MS patients had significantly elevated levels of major histocompatibility complex (MHC)-I-restricted EBV-specific TRB sequences compared to healthy donors in all human leukocyte antigen (HLA)-matched comparisons. In contrast, patients with NMOSD, MOGAD, or Susac’s Syndrome did not show this elevation when compared to HLA-matched healthy donors.
Specificity of EBV Response in MS
"Taken together, this study shows that the broader MHC-I-restricted EBV-specific TRB repertoire in MS patients is specific with regard to NMOSD, MOGAD and SuS, thereby further differentiating and defining these disease entities regarding their pathogenesis," Dr. Schneider-Hohendorf and colleagues wrote. The study suggests that the anti-EBV TRB repertoire is dynamic and can be detected using TRB bulk sequencing, even in small, heterogeneous patient cohorts.
Impact of MS Therapies on EBV Response
The researchers also investigated the impact of MS therapies on anti-viral T-cells. They analyzed data from healthy donors (n = 16) and MS patients (n = 198) treated with glatiramer acetate, interferon β, ocrelizumab (Ocrevus), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera). The study found that treatment with ocrelizumab, teriflunomide, or dimethyl fumarate resulted in a reduction of MHC-I-restricted EBV-specific TRB sequences. No such effect was observed in healthy donors, untreated MS patients, or those treated with glatiramer acetate or interferon β.
Clinical Implications and Future Directions
"The ability of MS treatments to decrease the breadth of the EBV-specific TRB repertoire... suggests that EBV and/or ineffective immune control of EBV might contribute to disease activity in MS," the authors noted. They suggest that further studies are needed to determine whether modulating the anti-EBV T-cell response could lead to clinical improvements in MS patients.
The study's limitations include its focus on T-cell receptor repertoire sequencing, specifically TRB, which limits the assessment of humoral adaptive immunity. The absence of paired α-β chain data also restricts the confidence in antigen-specificity. Additionally, the analysis only included unique TRB sequences from bulk samples, which reflects the immune response breadth but does not provide direct quantification of clonal cell frequencies or detailed functional and phenotypic assessments relevant to MS disease status.
