Multiple sclerosis and Epstein-Barr virus: what do we know?

Epstein-Barr virus (EBV) is our constant companion, infecting an estimated 90% to 95% of adults. Many of us first become infected as children, when the bacteria can cause cold and flu symptoms. EBV also causes mononucleosis, or the kissing disease, a glandular fever that has plagued lustful youth for generations.

After infection, EBV colonizes and remains in the body for a long time until death. Although EBV is thought to be mostly harmless, it is now thought to be implicated as a cause of several types of cancer. lymphoma and Nasopharyngeal tumor — and multiple sclerosis (MS). In 2022, groundbreaking research in science We suggested that previous EBV infection was the cause. Major Causes of MS.

Although the impact on current treatments is modest, deeper insight into the origins of MS could ultimately help neurologists better diagnose and treat patients, experts say. Says. The goal is to uncover clues that “will help us understand MS a little better and uncover insights that may lead to new disease-modifying therapies,” said Bruce, executive vice president of research for the National MS Society. Dr. Bebo said. Medscape Medical News In an interview.

EBV increases MS risk by 32 times

EBV was first associated with MS Back in 1981. For the 2022 study, researchers at Harvard T.H. Chan School of Public Health and Harvard Medical School analyzed serum from 10 million active-duty members of the U.S. military. They focused on his 801 MS recruits and matched them with more than 1,500 controls. All but one of the MS patients were infected with EBV. Infection appears to increase the risk of MS by 32 times (95% CI, 4.3-245.3; P < .001).

Michael Levy, M.D., a neurologist and associate professor at Harvard Medical School and Massachusetts General Hospital, said in an interview that the study results are “groundbreaking” and show that EBV is “likely the primary cause of MS. '', he said.

According to Levy, there are two main theories as to why EBV causes MS. The first hypothesis, known as the “molecular mimicry” theory, suggests that “EBV triggers MS, perhaps when the immune system mistakes viral proteins for myelin proteins and attacks myelin,” Levy said. said. In MS, the immune system attacks the protective myelin sheath and the axons it insulates.

“Beyond that point, eradicating the virus won't have much of an effect because the virus is no longer needed to maintain the disease and the immune response has already been triggered,” he said.

The second theory is that EBV is a driver of MS, and that the immune response to EBV continues throughout life, causing ongoing damage to the central nervous system. [CNS]. In theory, eradicating the virus could also eliminate the destructive immune response. Therefore, EBV antiviral therapy has the potential to treat, and perhaps even cure, MS,” Levy explained, adding that “removing pathogenic antigens is more effective than removing the immune response. It could be a strategic strategy.”

However, “we still don't know which hypothesis is correct,” he says. But “there is preliminary evidence in favor of each.”

“Additional fuses need to be lit”

It is also unclear why most people infected with EBV do not develop MS. According to , “additional fuses must be ignited” for the MS to become established. Explanation It comes with a landmark 2022 study.

“In terms of clinical implications, knowing whether a patient has a medical history or family history of mononucleosis can be a small clue, a small piece of evidence that helps in the diagnosis,” Bebo said.

He agreed with Levy that antiviral drugs could be a promising approach “if the problem with MS is a dysfunctional immune response to EBV.”

“We are excited to be able to provide the most effective treatment for our patients,” said Natalia Doros, MD, PhD, a postdoctoral fellow at the Harvard-MIT Center for Biomedical Engineering. Medscape Medical News Clinical trials of non-immunosuppressive antivirals targeting EBV in MS patients will be an important step toward a deeper understanding of the relationship between MS and EBV. “If antivirals are found to be effective in MS, we need to develop non-immunosuppressive therapies for MS patients as soon as possible,” she said.

Lawrence Steinman, MD, Professor of Neurology, Neuroscience, Pediatrics, and Genetics at Stanford University and co-author of the original commentary science The paper agreed that it was worth investigating whether antiviral therapy targeting EBV could benefit patients already suffering from MS. But he cautioned against clinicians conducting their own experiments outside of research studies. “We need to use the right antivirals and well-designed trials,” he said. Medscape Medical News.

Antiviral drugs may play an important role in MS control

Although there are no approved treatments for EBV, several MS disease-modifying therapies have anti-EBV effects, Levy said, citing anti-CD20 therapy as a clear example. Because the virus resides in the B cell compartment, it depletes B cells from circulation and depletes EBV. “Some MS drugs may have been unintentionally used as EBV antivirals,” he said.

Researchers are also looking at ways to use the MS-EBV link to prevent MS from developing in the first place, but there is still some uncertainty.

There may be some way to intervene in patients to treat EBV and prevent MS, perhaps including unique treatments for infectious mononucleosis (IM), Levy said.

The researchers are particularly interested in signs that the timing of infection may play a role in people infected with EBV via IM after early childhood, when the risk of developing MS is particularly high.a Learn German 2022 Although the risks for both groups were very small, it was calculated that those who developed IM were almost twice as likely to develop MS within 10 years compared to those who did not. Subgroup analysis revealed that the association between IM and MS was strongest in the infected group aged 14 to 20 years (hazard ratio, 3.52; 95% CI, 1.00-12.37). We also found that the association was stronger for men than for women.

author of 2023 Reviews in Clinical and Translational Immunology “Further understanding of IM may be important to unraveling the mystery of the role of EBV,'' they write. [in MS]. ”

Levy said this set of questions is important. “Theoretically, if we could know who is more likely to develop MS, or whose immune system is likely to respond to EBV and cause MS, we could intervene early and prevent neurological symptoms. You can search.”

But “remember that while most people in the world get an EBV infection, only 1 in 1,000 people get MS. Therefore, testing everyone before they develop neurological symptoms is a good idea. “It may not be realistic,” he said.

More questions to answer about EBV and MS

Researchers hope to answer several questions in the future. First, why does EBV have a unique relationship with MS? “With cross-reactivity with myelin, you might think that there are many viruses that can cause multiple sclerosis. , its relevance appears to be very limited to EBV,” Professor Levy said. “That's probably due to the fact that EBV is one of the only human viruses that can infect B cells, which play an important role in controlling the immune response.”

Molecular mimicry theory also opens up potential therapeutic pathways.

a 2022 survey Steinman et al. reported a “high-affinity molecular mimic between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM).” Antibodies against EBNA1 and GlialCAM are prevalent in MS patients. Researchers showed that in a mouse model of MS, EBNA1 immunization exacerbated the disease. The authors write, “Our results reveal the mechanism of the association between MS and EBV and may guide the development of new MS treatments.”

Could an EBV vaccine be the solution?

In terms of prevention, perhaps the most obvious question is whether the EBV vaccine can completely eliminate MS.

Bebo, of the National MS Society, said it will be important to determine which type of vaccine is best. Does it neutralize EBV infection? Or is it enough to prevent clinical symptoms?

Both types of vaccines are under development, and at least two clinical trials are currently underway. The National Institute of Allergy and Infectious Diseases Phase 1 study Study of adjuvanted EBV gp350-ferritin nanoparticle vaccine. A total of 40 subjects between the ages of 18 and 29 will participate, of whom 20 were infected with EBV and 20 were uninfected. The study is scheduled to be completed in 2025.

There is also a phase 1 placebo-controlled trial study A trial of an EBV vaccine based on mRNA-1189 is underway in 422 subjects aged 12 to 30 years. This trial is also scheduled to conclude in 2025.

“This is very interesting, but it may take 10 or 20 years to determine whether vaccines are effective in preventing multiple sclerosis,” Professor Levy said.

There were no disclosures for Levy, Steinman, Drosu, and Bebo.

Randy Dotinga is a freelance science or medical journalist and a board member of the Healthcare Journalists Association.