Epstein-Barr Virus Plays Critical Role in Multiple Sclerosis

Summary: Epstein-Barr Virus (EBV) may cause multiple sclerosis (MS) through higher levels of immune cross-reactivity than previously thought. Researchers found that T-cells targeting EBV can also recognize brain proteins, a misdirection seen in both MS patients and healthy individuals.

This suggests that the difference in immune cell function may determine why some develop MS after EBV infection. These findings deepen our understanding of EBV’s role in MS and point to potential targets for future therapies.

Key Facts:

  1. EBV-specific T-cells can mistakenly target brain proteins, contributing to MS.
  2. Cross-reactive T-cells are present in both MS patients and healthy people.
  3. The study highlights immune cell function as a key factor in MS development post-EBV infection.

Source: University of Birmingham

The role that Epstein-Barr Virus (EBV) plays in the development of multiple sclerosis (MS) may be caused a higher level of cross-reactivity, where the body’s immune system binds to the wrong target, than previously thought.

In a new study published in PLOS Pathogens, researchers looked at blood samples from people with multiple sclerosis, as well as healthy people infected with EBV and people recovering from glandular fever caused by recent EBV infection.

The study investigated how the immune system deals with EBV infection as part of worldwide efforts to understand how this common virus can lead to the development of multiple sclerosis, following 20-years of mounting evidence showing a link between the two.

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During testing of blood, the team also found evidence that cross-reactive T cells that target Epstein-Barr virus and central nervous system proteins are also present in many healthy individuals. Credit: Neuroscience News

While previous studies have shown that antibody responses to one EBV protein — EBNA1 — also recognise a small number of proteins of the central nervous system, this study found that T-cells, another important part of the immune system, that target viral proteins can also recognise brain proteins.

A second important finding was that these cross-reactive T-cells can be found in people with MS but also in those without the disease. This suggests that differences in how these immune cells function may explain why some people get MS after EBV infection.

Dr Graham Taylor, associate professor at the University of Birmingham and one of the corresponding authors of the study said:

“The discovery of the link between Epstein-Barr Virus and Multiple Sclerosis has huge implications for our understanding of autoimmune disease, but we are still beginning to reveal the mechanisms that are involved.

“Our latest study shows that following Epstein-Barr virus infection there is a great deal more immune system misdirection, or cross-reactivity, than previously thought.” 

“Our study has two main implications. First, the findings give greater weight to the idea that the link between EBV and multiple sclerosis is not due to uncontrolled virus infection in the body.

“Second, we have shown that the human immune system cross-recognises a much broader array of EBV and central nervous system proteins than previously thought, and that different patterns of cross-reactivity exist.

“Knowing this will help identify which proteins are important in MS and may provide targets for future personalised therapies.”

T Cells are involved

During testing of blood, the team also found evidence that cross-reactive T cells that target Epstein-Barr virus and central nervous system proteins are also present in many healthy individuals.

Dr Olivia Thomas from the Karolinska Institute in Sweden and joint corresponding author of the paper said:

“Our detection of cross-reactive T-cells in healthy individuals suggests that it may be the ability of these cells to access the brain that is important in MS.

“Although our work shows the relationship between EBV and MS is now more complex than ever, it is important to know how far this cross-reactivity extends to fully understand the link between them.”

About this EBV and Multiple Sclerosis research news

Author: Tim Mayo
Source: University of Birmingham
Contact: Tim Mayo – University of Birmingham
Image: The image is credited to Neuroscience News

Original Research: Open access.
3 Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis” by Graham Taylor et al. PLOS Pathogens


3 Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis


Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated.


Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens.


EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005).

In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP.


Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

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