Huge study reveals how Epstein-Barr virus may cause multiple sclerosis

There is growing evidence that the Epstein-Barr virus contributes to multiple sclerosis, and we are beginning to understand how. A study of more than 600,000 people found that the virus hijacks our immune cells, disrupting the normal functioning of the immune system, and activates genes that increase the risk of multiple sclerosis.

The virus – which most people get at some point in their lives, but few develop complications from – appears to particularly affect a type of immune cells called B cells, which produce antibodies against infections. “I think it’s very clear that this virus lives in B cells,” says Kate Attfield of the University of Oxford, who was not involved in the study. “It manipulates B cells to its own advantage.”

Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system goes wild and attacks healthy tissue. This involves other types of immune cells, called T cells, which enter the brain and cause widespread damage, particularly to the fatty substance that surrounds neurons. MS – which affects almost 2 million people worldwide – causes a wide range of symptoms, from vision and balance problems to tremors. In some people, symptoms wax and wane, while in others they get progressively worse.

Researchers have suspected the involvement of the Epstein-Barr virus (EBV) for decades, but it was difficult to prove because more than 90% of people are infected with EBV – which can cause “mono” or glandular fever – at any given time. It took a 2022 study of 10 million people to show that MS is much more likely in people who have had EBV than in those who have not.

The challenge is to understand why some people develop MS. A study published in January found a genetic effect: About one in 10 people carry variants that appear to predispose them to having more EBV in their body after infection, some of which were also associated with a higher risk of MS and other autoimmune diseases.

Now, researchers led by Yoshiaki Yasumizu of the Yale School of Medicine have taken a closer look at the impact of EBV.

The researchers, who declined to be interviewed, studied 617,186 people, gathered by the UK Biobank and a US study called All of Us. They all had their genome sequenced, from their blood and/or saliva, and submitted their medical records. Because EBV often lives permanently in the body once it has infected a person, researchers were able to detect its DNA.

Consistent with previous research, they found that a minority of people had significantly more EBV DNA than average: 1 percent of them carried 64 percent of the total EBV DNA from the blood collected in the studies.

The researchers then performed a genome-wide association analysis, looking for genetic variants associated with EBV vulnerability. They found 39 regions of the genome associated with EBV DNA. About a third of the associated variants were also linked to a risk of developing MS and severe disease.

Next, the team focused on B cells. Of nearly 471,000 B cells from 38 people, they found 1,069 infected with EBV. These cells behaved abnormally; for example, they highly expressed some of the genes linked to higher risk of MS and EBV DNA. Additionally, the infected B cells had activated signaling pathways that activate T cells, the same immune cells that attack the brain in MS.

A key question is what variants linked to EBV and MS risk actually do, says Ingrid Kockum of the Karolinska Institute in Stockholm, Sweden. She points out that the associations are not all in the same direction: some variants were associated with both higher EBV burden and higher MS risk, but others were associated with lower EBV levels but higher MS risk.

This suggests that the immune system can increase or decrease the risk of MS, depending on how it behaves. “If you have a high immune response, you may be able to keep the viral load low,” thereby reducing your risk of MS, says Kockum. A variant that weakens the initial antibody response would therefore be associated with both higher EBV levels and a higher risk of MS.

Certain genetic variants could lead to “an exacerbated immune response that then tips you over the edge” [into MS]” adds Attfield, while others might mean that “a person’s immune system isn’t doing a very good job of handling the virus,” leading to a higher viral load that could also contribute to MS. “It’s very difficult to prove one or the other,” she says.

In the long term, different research groups want to develop treatments for MS. Immune cells that fight EBV have shown promise as a treatment, and vaccines against EBV are being developed that may also be protective.

However, Attfield cautions that we need to know more about how the disease progresses. Addressing EBV may help prevent MS, but it is less clear whether this would be beneficial once the process is already underway. Indeed, we do not know whether MS persists on its own beyond a certain point or whether it is always driven by the virus. “[EBV] may, at this point, have nothing to do with it, or it may be intrinsic to it,” says Attfield.