Unravelling the link between Epstein-Barr virus and multiple sclerosis

For decades, scientists have known that infection with the Epstein-Barr virus (EBV) is one of the strongest risk factors for developing multiple sclerosis (MS). But an important question has remained: How does a virus carried by more than 90 per cent of adults contribute to a disease that affects only a small fraction of people?

A new review led by Dr. Jan Lünemann, UBC Chair in Multiple Sclerosis and Autoimmune Neurology Research and Director of the MS and Neuromyelitis Optica Program at the Djavad Mowafaghian Centre for Brain Health, explores recent breakthroughs that are helping answer this question. Published in The Lancet Neurology, the review highlights how research has moved beyond simply identifying a link between EBV and MS to uncovering how the virus may contribute to disease and how these discoveries could lead to new treatments and prevention strategies.

“We now know that EBV can trigger immune responses that mistakenly recognize proteins in the brain, reshape B cell biology in ways that promote autoimmunity and potentially sustain chronic immune activation within the brain and spinal cord,” says Dr. Lünemann, who was recently featured on The Lancet Neurology’s podcast. “The challenge now is to understand precisely how it drives disease susceptibility and how these insights can be translated into therapies or perhaps even preventive strategies.”

A common virus with an uncommon consequence

EBV is one of the world’s most widespread viruses, most commonly known for causing mononucleosis, or “mono.” After infection, it remains in the body for life by hiding inside memory B cells, a type of immune cell that helps the body respond to infections.

While most people infected with EBV remain healthy, studies over the past several years have established the virus as the strongest known environmental risk factor for MS. A landmark 2022 study found that the risk of developing MS increased more than 30-fold following EBV infection.

However, infection alone does not cause MS. Genetics, environmental factors (such as obesity, lower vitamin D levels and smoking) and the way a person’s immune system responds to EBV all appear to influence whether the disease develops.

“EBV infection appears to be necessary, but not sufficient to cause MS,” says Dr. Lünemann. “MS results from the convergence of several risk factors rather than a single cause.”

Understanding how EBV may drive MS

The review highlights several ways EBV may contribute to MS. One possibility is that immune responses designed to fight the virus may mistakenly attack the brain and spinal cord. Another is that EBV may alter B cells, causing some to become overly active and move into the central nervous system, where they can trigger inflammation.

Recent research led by Dr. Lünemann, published in Annals of Neurology, provides further evidence that the immune response to EBV may be directly involved in MS. The study found that people with MS produce EBV-targeting antibodies that are not only higher in number but also behave differently. Compared with healthy individuals, EBV-specific antibodies in people with MS showed enhanced inflammatory activity, making them more effective in activating immune cells. This heightened activity was linked to signs of active disease, including relapses and brain inflammation.

The findings suggest that the body’s response to EBV, not just the presence of the virus itself, may influence MS development and progression.

New possibilities for treatment and prevention

A better understanding of EBV’s role in MS is opening the door to new treatment strategies. Researchers are exploring approaches that target the virus itself, including vaccines, antiviral therapies and treatments that remove harmful EBV-infected immune cells. Many of these approaches are still in early stages, but they represent a shift from simply understanding the connection between EBV and MS to developing ways to prevent disease.

Dr. Lünemann identified four key priorities for future research: conducting longitudinal  studies in people at high risk of developing MS to identify early EBV-related changes before symptoms appear; developing better biomarkers to determine who may have harmful immune responses to EBV and who may benefit from targeted therapies; advancing clinical trials of EBV-focused treatments; and determining whether EBV only contributes to the initial development of MS or continues to drive disease activity and progression after diagnosis.

“We need to move from associations to mechanisms, and from mechanisms to therapy and prevention,” says Dr. Lünemann. “If EBV is indeed a necessary step in the pathway to MS, then preventing or reshaping the immune response to EBV could become one of the most important opportunities we have, not only to treat MS more effectively, but perhaps one day to prevent it altogether.”