EBV reprograms autoreactive anti-CNS B cells as antigen presenting cells in multiple sclerosis
Posted on: 4 June 2026
Preprint posted on 12 February 2026
How Epstein-Barr virus reshapes the B cell landscape in Multiple Sclerosis
Selected by Léa Bastien, Matthias Krull, Nathan Chochon, Jérémy Smili, uMontreal Neuro preLighters
Categories: immunology, neuroscience, pathology
Background
Multiple sclerosis (MS) is the most widespread demyelinating autoimmune disease of the central nervous system (CNS), affecting more than 2.8 million people in the world. MS manifests primarily in relapsing-remitting form and is characterized by chronic inflammation, demyelination and progressive neurodegeneration.The mechanisms underlying MS development are still poorly understood, though involve complex interactions between genetic and environmental factors.
Epstein-Barr virus (EBV) infection is recognized as the environmental risk factor most strongly associated with MS. A longitudinal study demonstrated that EBV infection increases the risk of developing MS more than 30-fold in young adults, with no specific age identified within this population. Complementary work attempted to better understand the mechanism of sensitization to multiple sclerosis after contracting the EBV virus. These studies identified several potential mechanisms, including molecular mimicry between EBNA1 and CNS autoantigens, episodic virus reactivation associated with relapses, and deficient immune surveillance of infected B cells.
To date, therapies mainly target B lymphocytes, which play a central role in the disease, as demonstrated by anti-CD20 antibodies such as rituximab and ocrelizumab, which significantly reduce disease activity.
This study seeks to establish consensus on the cause of patients’ vulnerability to developing MS after EBV infection. It was set up to allow us to define a framework for future research and thereby serve as a foundation for all studies interested in the influence of EBV contraction on multiple sclerosis.
Key Findings
This study provides a mechanistic framework linking EBV infection to MS, showing that EBV contributes to the functional reprogramming of autoreactive B cells and addressing a key gap in MS pathogenesis.
A major strength lies in the methodological approach, which overcomes the low abundance and detectability of EBV-infected B cells. The development of EBV-seq enabled sensitive detection of viral transcripts at the single-cell level, allowing identification and characterization of EBV⁺ B cells in blood and cerebrospinal fluid beyond what was previously achievable with standard methods.
EBV preferentially infects a pathogenic B-cell subset in MS
The study shows that EBV-infected (EBV+) B cells are enriched in MS and predominantly localize within a CD27+ CD21low memory B-cell subset associated with pathogenic immune responses. The authors used a multimodal single-cell approach and analyzed over ~876,000 B cells from blood and cerebrospinal fluid. EBV⁺ B cells were more frequent in MS than in healthy controls and were not randomly distributed across B-cell populations.
EBV reprograms B cells into pro-inflammatory antigen-presenting cells
Comparing EBV⁺ and EBV⁻ B cells, the authors found that EBV infection induces strong upregulation of B-cell activation, antigen presentation, and interferon signalling pathways. Using differential expression analyses and module scoring, they show that EBV⁺ B cells acquire a pro-inflammatory antigen-presenting cell phenotype, indicating active functional reprogramming by the virus.
EBV⁺ B cells are autoreactive and cross-react with viral and CNS antigens
Recombinant antibodies derived from EBV⁺ B cells revealed that over 25% bind central nervous system tissue. Importantly, some antibodies bind both EBV antigens and CNS autoantigens, supporting a molecular mimicry mechanism linking viral infection to autoimmunity.
EBV⁺ B cells drive pathogenic immune responses
Using an in vitro co-culture system, EBV⁺ B cells loaded with brain antigens activated T peripheral helper cells and induced expansion of autoreactive EBV⁻ plasmablasts producing CNS-reactive antibodies. This provides functional evidence that EBV⁺ B cells act as driver cells that amplify autoimmune responses.
Why we highlight this preprint
We chose this study because, as neuroscience students, we are fascinated by neuropathology, especially neurodegenerative diseases such as multiple sclerosis. As a result, articles that make a significant contribution to the field of research by offering new insights into the relationship between the environment and the onset of these diseases captivate us.
Furthermore, having recently taken classes on multiple sclerosis, the link between EBV and the disease remained a mystery to us. This preprint caught our eye because it seemed to answer this question very elegantly.
Finally, we really appreciated how this study managed to cross several disciplines before validating their conclusions, which grants the paper more reliability.
Questions for the authors
Your study highlights the central role of EBV-infected B cells in activating autoimmune responses directed against the central nervous system. Given the clinical efficacy of B-cell depletion therapies in multiple sclerosis, do you think that their benefits could be partly explained by the elimination of these EBV-infected B cells?
Given that the average frequency of EBV+ B cells is significantly lower in MS than in lupus, have you performed a sensitivity analysis to justify the identical threshold of 2 UMI for MS and lupus?
Considering your results and the central role of memory B lymphocytes in the vulnerability and the appearance of MS: What role do you think that deficiencies (such as vitamin D), commonly recognized as vectors of vulnerability to inflammation, would have on the triggering of the disease? Can your therapeutic lead be effectively added to other therapies already recognized by the FDA?
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