How the Epstein-Barr virus triggers multiple sclerosis: the mechanism discovered by researchers

For the first time, researchers have succeeded in identifying the mechanism by which the Epstein-Barr virus (EBV) — one of the most widespread viruses in the world — can trigger multiple sclerosis in certain individuals. The discovery was published in the journal Science Translational Medicine and also sheds light on how some immunotherapies manage to slow the progression of the disease.

EBV belongs to the herpesvirus family and infects approximately 90% of the world's population. In most people it produces no significant symptoms or remains dormant throughout life, but it is well known as the primary cause of infectious mononucleosis, commonly called "the kissing disease".

For over 20 years, specialists have suspected that EBV plays an important role in the development of multiple sclerosis (MS), yet the exact mechanism had remained unknown. Natalia Drosu, a neurologist at Massachusetts General Hospital and co-author of the study, explained: "It is well established that the Epstein-Barr virus is one of the main causes of multiple sclerosis in a certain group of people."

What happens in the body of people with multiple sclerosis

Multiple sclerosis is an autoimmune disease in which the immune system mistakenly attacks the myelin sheath — the protective layer surrounding nerve fibres in the brain and spinal cord. Damage to myelin disrupts the transmission of nerve signals and can cause vision problems, difficulty walking, balance disorders, numbness, muscle weakness, and impaired cognitive function.

Worldwide, an estimated 2.9 million people are living with multiple sclerosis. The disease currently has no curative treatment, but existing therapies can reduce the number of relapses and slow the progression of the condition.

The key role of CD4+ T cells

To decipher the link between the virus and the disease, the research team analysed the immune system's response to EBV. They found that the activity of CD4+ T cells — a type of lymphocyte that coordinates the immune response — was approximately twice as intense in patients with multiple sclerosis compared with healthy individuals.

When scientists sequentially eliminated different types of T cells during experiments, the immune response against the virus decreased significantly only when CD4+ T cells were removed. This suggests that these cells play the primary role in triggering the autoimmune reaction. According to the authors, EBV stimulates these cells, which subsequently participate in the attack on the central nervous system.

Emily Edwards, a researcher at Monash University in Australia, praised the findings: "These discoveries show that we are beginning to understand how the Epstein-Barr virus causes multiple sclerosis to develop."

The link with existing treatments

The study also examined how two important categories of drugs used in treating multiple sclerosis work.

The first is frexalimab, still in clinical development, which reduces inflammation and nerve damage by blocking the activity of CD4+ T cells.

The second category comprises anti-CD20 therapies, already in use for several forms of multiple sclerosis. These destroy B lymphocytes — the cells that the Epstein-Barr virus infects and in which it can remain dormant for years.

The researchers monitored 60 patients with multiple sclerosis, both before commencing anti-CD20 treatment and after six months of therapy. The level of CD4+ T cells fell by approximately 2.5 times, and the effect was maintained for at least one year — a result subsequently confirmed in a second group of patients.

Furthermore, treated patients had lower levels of the Epstein-Barr virus in their saliva compared with both healthy individuals and untreated patients.

Why viral activity decreases

The researchers' explanation is that anti-CD20 therapies eliminate a large proportion of the B lymphocytes infected with the virus. With fewer B cells presenting viral fragments to the immune system, CD4+ T cells receive fewer activation signals, and the immune reaction is dampened.

Emily Edwards emphasised: "This demonstrates the importance of both groups of immune cells in triggering the disease and how immunotherapies can reduce its severity."

A discovery that builds on earlier research

This new study adds to a series of major findings in recent years concerning the link between EBV and multiple sclerosis. In 2022, a large study published in the journal Science, which followed more than 10 million US military personnel over two decades, showed that the risk of multiple sclerosis increases more than 30-fold following infection with the Epstein-Barr virus — considered at the time the strongest evidence of the link between the infection and the disease.

The recent research goes further, explaining the mechanism by which the virus provokes the immune reaction and why drugs that act on B and T lymphocytes succeed in reducing inflammation and relapses.

The study's authors believe that the findings could, in future, contribute to the development of therapies and vaccines against the Epstein-Barr virus, which might reduce the risk of multiple sclerosis developing in individuals with a genetic predisposition. Whilst this does not represent a curative treatment, the discovery constitutes one of the most significant recent advances in understanding the mechanisms underlying multiple sclerosis.