Epstein-Barr virus plays a crucial role in multiple sclerosis

Summary: The Epstein-Barr virus (EBV) may cause multiple sclerosis (MS) through a higher level of immunological cross-reactivity than previously thought. Researchers found that T cells directed against EBV can also recognize brain proteins, a misrouting observed in both MS patients and healthy individuals.

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

Important facts:

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

Source: University of Birmingham

The role played by the Epstein-Barr virus (EBV) in the development of multiple sclerosis (MS) may be due to greater cross-reactivity than previously thought, in which the body's immune system binds to the wrong target.

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

The study examined how the immune system deals with EBV infection and is part of a global effort to understand how this widespread virus can lead to the development of multiple sclerosis, after 20 years of mounting evidence of a link between the two diseases.

In blood tests, the team also found evidence that cross-reactive T cells targeting the Epstein-Barr virus and central nervous system proteins are also present in many healthy individuals. Image credit: Neuroscience News

While previous studies showed that antibody responses to an EBV protein – EBNA1 – also recognize a small number of central nervous system proteins, this study found that T cells, another important part of the immune system that attacks viral proteins, can also recognize brain proteins.

A second important discovery was that these cross-reactive T cells can be found in both people with MS and people without the disease, suggesting that differences in how these immune cells work may explain why some people develop MS after EBV infection.

Dr Graham Taylor, Associate Professor at the University of Birmingham and one of the study’s corresponding authors, said:

“The discovery of the link between the Epstein-Barr virus and multiple sclerosis has enormous implications for our understanding of autoimmune diseases, but we are still at the very beginning of uncovering the underlying mechanisms.

“Our latest study shows that there is much more immune system dysfunction or cross-reactivity following infection with the Epstein-Barr virus than previously thought.”

“Our study has two major implications. First, the results support the assumption that the link between EBV and multiple sclerosis is not due to an uncontrolled viral infection in the body.

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

“This knowledge will help us to identify which proteins are important in MS and could provide starting points for future personalized therapies.”

T cells are involved

In blood tests, the team also found evidence that cross-reactive T cells that target the 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 co-author of the article said:

“Our discovery 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 that the relationship between EBV and MS is more complex today than ever before, it is important to know how far this cross-reactivity extends to fully understand the connection between them.”

About this research news on EBV and multiple sclerosis

Author: Tim Mayo
Source: University of Birmingham
Contact: Tim Mayo – University of Birmingham
Picture: The image is from Neuroscience News.

Original research: Open access.
“3 Increased immunity to Epstein-Barr virus and potential cross-reactivity in multiple sclerosis” by Graham Taylor et al. PLOS pathogens


3 Increased immunity to the Epstein-Barr virus and possible cross-reactivity in multiple sclerosis


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


Untreated individuals with relapsing-remitting MS, POST-IM individuals and HC were matched, where possible, by gender, age and HLA-DRB1*15:01EBV 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 tested against 9 new modified vaccinia Ankara viruses (MVA) expressing putative CNS autoantigens.


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

In Ex vivo In assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 remained 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 were found to be common targets, including MOG, MBP, PLP, and MOBP.


Increased EBV-specific antibody responses in the serum of the MS group extended beyond EBNA1, suggesting greater dysregulation of EBV-specific antibody responses than previously thought. Differences in T cell responses to EBV were more difficult to detect, however stimulation of EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed high levels of autoreactivity, suggesting a broad capacity of the virus-induced T cell compartment to damage the CNS.