What Does the Epstein-Barr Virus Have to Do With Multiple Sclerosis?

While the cause of multiple sclerosis (MS) is still unknown, it is generally believed that genetic susceptibility and environmental factors both play a role.

Among of the environmental factors that have been studied at some length are certain kinds of infection, particularly infection by the Epstein-Barr virus (EBV), which is part of the human herpesvirus family of infectious diseases.

Indeed, multiple studies suggest that EBV, the most common cause of mononucleosis, or “mono” (often called “the kissing disease” because it’s transmitted via saliva or mucus), may play a role in the development of MS.

Now, a study published in October 2021 by JAMA Network Open, which included nearly 2.5 million people, found that those diagnosed with infectious mononucleosis, an acute illness most commonly caused by EBV (though it’s linked with other viruses as well), during childhood were nearly twice as likely to develop MS. And for people diagnosed with infectious mononucleosis during adolescence, the risk of MS was three times higher, according to the researchers.

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EBV Stays for Life

Researchers at the University of British Columbia in Vancouver (UBC), led by Marc Horwitz, PhD, have been studying the relationship between MS and EBV closely to see if it can offer clues as to how to diagnose MS earlier and, ultimately, treat it more effectively. Dr. Horwitz is the Sauder Chair of Pediatric Virology and a co-leader of the Infection, Inflammation, and Immunity Research Group at UBC.

More than 90 percent of people worldwide will be infected with EBV by age 35, according to the American Academy of Family Physicians (AAFP).

In children, EBV usually looks like a mild, brief illness. But in up to 50 percent of teenagers and young adults, it can show up as infectious mononucleosis and cause extreme fatigue and other flu-like symptoms that can last for weeks, the AAFP says.

“Most of us in North America and Europe get mononucleosis as a result of exposure to EBV, typically in our teens or early twenties,” says Horwitz.

“But what a lot of people don’t know is that EBV stays in our bodies for the rest of our lives. And though it may be dormant and not causing new infection or illness, our body’s response to it may be affecting other aspects of our health,” he says.

It’s possible that those who get an EBV infection that’s initially more active — including those who experienced infectious mononucleosis in childhood or adolescence — have an increased risk of MS later in life, Horwitz adds.

Links Between EBV and MS

While epidemiological studies suggest that some 95 percent of people in the general population have evidence of exposure to EBV in their blood, that percentage is closer to 100 percent among those who have MS.

“Anecdotally, we also know that people with MS typically had more severe cases of mononucleosis than those without MS,” Horwitz says.

And the relationship may not end there.

A study by Horwitz and his team, published in November 2020 in Frontiers in Immunology, observed that mice infected with a herpesvirus similar to EBV (mice can’t get EBV) had high levels of the virus in their B cells — white blood cells that produce antibodies to fight infection. Mice with high levels of the virus in their B cells experienced more severe symptoms of experimental autoimmune encephalomyelitis, essentially a form of MS in mice.

The researchers found that those mice developed a disease reminiscent of MS, with MS-like brain lesions and loss of balance.

“There’s no evidence that EBV is more active in people with MS,” Horwitz says. “However, if you test people without MS for EBV, even with extremely accurate tests, it would be undetectable. In people with MS, it’s detectable.”

This finding builds on an earlier analysis published by Horwitz’s UBC colleagues that identified several studies that observed links between EBV and the risk of developing relapsing-remitting MS (RRMS). The association with primary progressive MS (PPMS) was less clear.

Immune System Overreaction

Horwitz and his team, among others, believe these findings may indicate that the immune systems of those with MS have a history of “overreacting” to their initial EBV infection, with their B cells producing higher levels of anti-EBV antibodies, compared with those who don’t have MS. This can have benefits in terms of fighting infections, but it may also be detrimental in terms of susceptibility to autoimmune diseases such as MS.

Specifically, EBV seems to have a profound effect on a type of B cells called ABCs, or age-associated B cells. As the name indicates, ABCs accumulate as people age. However, people with MS have higher levels of ABCs at a younger age, perhaps driven by EBV, Horwitz explains.

Additional studies from other researchers have also found that people with RRMS have higher levels of the human herpesvirus antibody immunoglobulin M, and that people with a history of another herpesvirus, varicella zoster (more commonly known as chickenpox), may have an increased risk of RRMS.

Horwitz and his team are now looking at ways in which the presence of these ABCs can potentially be used to identify people at risk of certain forms of MS. There appears to be a similar relationship between ABCs and other autoimmune disorders, including rheumatoid arthritis (RA) and lupus, he says.

The team’s findings on RA and EBV were published in June 2021 in the online scientific journal eLife.

Hope for Treatment and Prevention

For all of these autoimmune diseases, understanding the role of EBV in their development could help shape research into new treatments, according to Horwitz. More important, as research reveals the role EBV may play in these diseases, as well as certain forms of cancer, it could push efforts to develop a vaccine against the virus, he says.

“What we’re trying to do is understand the changes that are happening to the cells in the bodies of people with MS that are holding EBV,” Horwitz explains. “If we can identify those cells, we have a potential way to determine a person’s risk for developing MS. If we can identify and get rid of those cells, we may have a cure for MS.”

“But you still have to be genetically susceptible to MS to get it,” he adds. “You’re not going to get MS simply because you had EBV when you were younger. Otherwise, more of us would have MS. However, what we think is that EBV may provide a key to a better understanding of MS and how it develops, and that can only help people with MS.”