Epstein-Barr Virus Immune Response Specific to Multiple Sclerosis Relative to Other Demyelinating Diseases

A cross-sectional study showed that the putatively aberrant immune response directed against Epstein-Barr virus (EBV) was specific to multiple sclerosis (MS) in relation to other similar demyelinating disorders such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and Susac’s Syndrome (SuS). Presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark, these findings suggest this response was specifically altered by treatments meddling with EBV hosts cells or activated lymphocytes.^1,2

The late-breaking study, which was also published in Brain, featured 1317 peripheral blood T-cell receptor β chain (TRB) repertoire samples of healthy donors (HD; n = 409), patients with MS (n = 710) before and after treatment, patients with NMOSD (n = 87), MOGAD (n = 64), and SuS (n = 47) for presence of unique EBV-specific TRB sequences. Notably, patients with MS presented with elevated major histocompatibility complex (MHC)-I-restricted EBV-specific TRB sequences compared with HD in all human leukocyte antigen (HLA)-matched comparisons performed by researchers. Moreover, the same number of HLA-matched patients with either NMOSD, MOGAD, or SuS did display elevation of EBV-specific TRB sequences compared with HLA-matched HD.

“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,” lead author Tilman Schneider-Hohendorf, PhD, postdoctoral fellow in the department of neurology at Münster University Hospital in Germany, and colleagues wrote.² “The anti-EBV TRB repertoire can be subject to dynamics that have rarely been detected with previous technologies that directly assess the virus or subsequent immune responses in peripheral blood.”

In this analysis, investigators also assessed the utility of TRB repertoire sequencing in recognizing EBV infection status by evaluating longitudinal datasets of 2 MS cohorts that underwent autologous hematopoietic stem cell transplantation. Authors reported that EBV-specific CD8+ TRB sequences spiked among patients with high EBV viral loads and compared with baseline, patients displayed elevated sequence matches at 6, 24, and 36 months of longitudinal follow up. Researchers noted that these results suggest that quantification of MHC-I-restricted EBV-specific CD8+ TRB sequences can envision the dynamics of the anti-EBV T-cell response beside immune reconstitution.

Top Clinical Takeaways

Patients with MS display elevated EBV-specific T-cell receptor sequences compared with NMOSD, MOGAD, and SuS.
Treatments like ocrelizumab, teriflunomide, and dimethyl fumarate reduce EBV-specific T-cell responses in MS.
The study highlighted the potential of targeting the EBV-specific immune response to impact MS disease activity.

Furthermore, researchers assessed the potential influence of MS therapies such as glatiramer acetate (GA Depot), interferon β, ocrelizumab (Ocrevus; Roche), teriflunomide (Aubagio; Sanofi), or dimethyl fumarate (Tecfidera; Biogen) on anti-viral T-cells in HD (n = 16) and patients with MS (n = 198) from different cohorts. Among the patients with MS, 24 of them stayed untreated after the baseline sampling and 174 were started on different treatment regimens. The study showed that treatment with either ocrelizumab, teriflunomide, or dimethyl fumarate resulted in a reduction of MHC-I-restricted EBV-specific TRB sequences. Notably, authors did not observe a longitudinal effect in HD, in untreated patients with MS, or in patients with MS treated with either glatiramer acetate or interferon β.

“Concerning viral load or EBV-specific serum antibodies, most evidence lies with infection status and not necessarily dynamic changes. It also proves that TRB bulk sequencing is sufficiently sensitive to detect subtle differences in T-cell anti-viral immune responses in small, heterogeneous patient cohorts. This allows analysis of rare diseases as well as monitoring of putative treatment effects,” Hohendorf et al noted.² “The ability of MS treatments to decrease the breadth of the EBV-specific TRB repertoire, either by depleting host cells, by interfering with viral replication or with activated cells, suggests that EBV and/or ineffective immune control of EBV might contribute to disease activity in MS. Additional studies are needed to evaluate whether specific modulation of the anti-EBV T-cell response could be directly linked to clinical improvement in MS patients.”

This analysis focused on the T-cell receptor repertoire, specifically sequencing only TRB, which authors noted limited the study’s application to humoral adaptive immunity. Researchers underscored that full confidence in antigen-specificity would need paired α-β chain data, which was not accessible at the time. The absence of MHC-II-restricted, EBV-specific TRB sequences also restricted the results to CD8+ T-cells, not including conclusions on CD4+ T-cell responses. In addition, authors only analyzed unique TRB sequences from bulk samples, which reflected the immune response breadth, but did not provide direct quantification of clonal cell frequencies or detailed functional and phenotypic assessments relevant to MS disease status.