Slowly tracing the pathway from Eppstein-Barr virus to multiple sclerosis.

The idea that MS is caused by a microbe is almost as old as the very first description of the disease by Jean-Martin Charcot in the nineteenth century. It was first proposed by Pierre Marie, his successor. While there was no concrete evidence to support it at the time, given that the concept of microorganisms was extremely new,¹ the role of one virus – the Epstein-Barr virus (EBV) – has become increasingly clear over the last few years.

Discovered in the 1960s by Michael Epstein and Yvonne Barr, EBV was the first virus to be associated with non-communicable medical diseases, playing a major role in the development of various lymphomas.  Like all herpes viruses, such as cold sores, EBV persists in a latent form in the body following infection. EBV’s primary ‘hiding place’ are memory B cells. These cells work within our adaptive immune system to fight off infection, such as by triggering the production of antibodies.²

The link between EBV and MS was made as early as the 1980s. For instance, we know that an EBV infection that causes symptoms of glandular fever more or less triples the risk of MS.

However, it was only in 2022 that a large epidemiological study yielded compelling evidence that EBV is a vital prerequisite to developing MS.³ It is estimated that 90% of all people in our region will become infected with EBV, but only 0.1% will go on to develop MS.⁴ Just like lymphoma, we can consider MS to be a rare complication of an EBV infection that develops in cases in which genetic predisposition and other external factors are also unfavourable. It is not known how EBV contributes to the development of MS, nor why it affects some people and not others. Over the past four years, scientists have worked tirelessly to trace this mechanism. 

Results of immunological and virological research appear to indicate that people with MS have mildly weaker ‘control’ mechanisms of EBV. As a result, the virus is slightly more active in the B cells and more likely to reactivate. Our immune system must therefore work harder to contain the virus, leading to higher anti-EBV antibodies in the blood.^5,6 This leads us seamlessly into the two major hypotheses that seek to explain the underlying mechanism.

Alongside their role as a primary site of EBV, B cells also play a pivotal role in the central nervous system’s autoimmune response in MS. Various modern MS drugs target B cells. If EBV resides in a B cell, it changes the cell. For instance, the virus will produce membrane proteins that interact with other immune cells, or transcription factors that bind with endogenous DNA. In this way, EBV influences a B cell’s normal immune functions. It may be that EBV uses this mechanism to throw off the delicate balance between our body’s defences against infection and autoimmunity. In fact, recent animal testing suggests that EBV could influence B cells to migrate into and damage the central nervous system.⁷

Another hypothesis proposes that the problem isn’t caused by EBV in and of itself, but by our immune system’s furious attempts to contain EBV. Various researchers have demonstrated an intriguing similarity between the viral protein EBNA-1 and different endogenous proteins in the central nervous system. It is therefore possible that an immune response misfire against EBNA-1 may also target our own tissues, leading to MS.⁸

Both hypotheses are undergoing extensive further research, but aren’t completely mutually exclusive. At the same time, another important question remains as yet unanswered: whether EBV merely triggers the illness, or also plays an active role during disease progression.

What is certain is that scientists around the world are working hard to trace the pathway leading from initial EBV infection to MS. Time will tell whether this will help us to better predict disease activity, provide more targeted MS therapy or perhaps even prevent the disease.

Dr Dries De Wit

UZ Leuven – KU Leuven

‍

1. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci. Feb 1 2009;277 Suppl 1:S3–8. doi:10.1016/S0022-510X(09)70003-6

2. Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD. The immunology of Epstein-Barr virus-induced disease. Annu Rev Immunol. 2015;33:787–821. doi:10.1146/annurev-immunol-032414-112326

3. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. Jan 21 2022;375(6578):296–301. doi:10.1126/science.abj8222

4. Lunemann JD, Munz C. Epstein-Barr virus and multiple sclerosis: from associations to mechanisms to potential therapies. Lancet Neurol. Aug 2026;25(8):755–763. doi:10.1016/S1474-4422(26)00177-8

5. Meloni C, Marnetto F, Fagnani C, et al. EBV Dysregulation Is Associated With Immune Imbalance in Multiple Sclerosis: Evidence From Integrated Viral and Host Analyses. Neurol Neuroimmunol Neuroinflamm. Mar 2026;13(2):e200545. doi:10.1212/NXI.0000000000200545

6. Munz C. Altered EBV specific immune control in multiple sclerosis. J Neuroimmunol. May 15 2024;390:578343. doi:10.1016/j.jneuroim.2024.578343

7. Laderach F, Piteros I, Fennell E, et al. EBV induces CNS homing of B cells attracting inflammatory T cells. Nature. Aug 6 2025;doi:10.1038/s41586-025-09378-0

8. Thomas OG, Olsson T. Mimicking the brain: Epstein-Barr virus and foreign agents as drivers of neuroimmune attack in multiple sclerosis. Front Immunol. 2023;14:1304281. doi:10.3389/fimmu.2023.1304281