“With MS you just run out of fuel. JUST STOP. You can’t even go on. You can’t even talk."
- Ann Romney, Global Ambassador, Ann Romney Center for Neurological Diseases, Brigham and Women’s Hospital
“I long for the day when MS stands for Mystery Solved.”
- Lisa D. Graham, MS Patient
Researchers have long suspected a link between multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), and Epstein-Barr virus (EBV), a ubiquitous virus that infects almost everyone. In January of this year, two publications ignited major excitement, especially among investigators who’ve touted this link. One report appeared in Science showing a remarkable association between EBV and the development of MS. The second, published in Nature, provided insight into a mechanism that could explain how EBV causes the immune system to mistakenly target the CNS, thus resulting in MS. In this Germ Gems post, I provide an overview of these new developments.
Synopsis of MS. MS is a potentially disabling disease of the brain and spinal cord (the CNS). It is an autoimmune disease, that is the immune system attacks its own tissues—in the case of MS, the protective sheath (myelin) that covers nerve fibers, which causes communication problems between the brain and the rest of the body. Eventually, the disease can result in permanent damage or deterioration of the nerves.
Signs and symptoms of MS vary considerably and depend on the amount of nerve damage and which nerves are affected. Common symptoms include debilitating fatigue, blurred or double vision, numbness, lack of coordination, slurred speech, and depression. Some people with severe MS may lose the ability to walk, while others may experience long periods of remission without any new symptoms. There is no cure for MS. Treatments, however, can help speed recovery from attacks and help manage symptoms.
In America, nearly 1 million adults are living with MS, and the prevalence is steadily increasing. The disease afflicts four times as many women as men, and the risk is greater at higher latitudes than in places close to the equator. Some experts attribute this geography-associated risk to reduced sun exposure with concomitantly lower vitamin D levels in northern climes.
Synopsis of EBV. EBV was discovered in 1964. It’s a double-stranded DNA virus that belongs to the Herpes family. EBV is the cause of infectious mononucleosis (IM), a common infection worldwide with a lifetime prevalence of greater than 90%. EBV is commonly transmitted by infected saliva (hence IM’s nickname, the “kissing disease”). At least one out of four teenagers and young adults who get infected with EBV will develop IM, a self-limited disease characterized by fever, sore throat, fatigue, and enlarged lymph glands.
Most infected people have asymptomatic EBV infections and are unaware that they harbor the virus. EBV remains latent in their B lymphocytes for life. Latent EBV infection is a factor in the development of certain kinds of cancer, especially in immunocompromised individuals. Over the past several decades, multiple studies implicated EBV as a cause of MS. A major conundrum, however, has been the fact that while over 90% of people are infected by EBV, only a tiny fraction develops MS.
Results of recent studies. To explore the potential link between EBV and MS, a team of researchers at the Harvard T.H. Chan School of Public Health led by epidemiologist Dr. Alberto Ascherio carried out a large and very interesting study. They took advantage of more than 10,000 serum samples from active-duty US military personnel collected between 1993 and 2013 that were stored in the Department of Defense Serum Repository. From these samples, they determined whether—and when—donors were infected with EBV. They also sampled serum from more than 1,500 matched controls (people with similar characteristics who did not develop MS).
As reported in their January 13, 2022 Science paper, “Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis,” Ascherio’s team found a much higher rate of EBV infection among people who developed MS than among controls. Out of the 801 MS cases, only one person tested negative for EBV in their final serum sample collected before the onset of MS. The researchers calculated that people infected with EBV were 32 times as likely to develop MS as uninfected people.
These researchers also found no such association between MS and other viruses, including cytomegalovirus, another member of the Herpes family. Additionally, they assayed the serum samples for a biomarker of nerve degeneration and found elevated levels only in MS patients, and only after their EBV infection.
A second study published on January 24, 2022 in Nature, “Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM,” shores up the hypothesis that EBV causes MS. In this study, a research team at Stanford University led by professor William Robertson, M.D., Ph.D. showed that about 20% to 30% of patients with MS have antibodies in their blood that bind tightly to both a protein from EBV, called EBNA1, and to a protein in the CNS, called the glial cell adhesion molecule, or GlialCAM. This means that when the immune system attacks EBV to clear the virus, it also ends up targeting GlialCAM in myelin. This phenomenon, called molecular mimicry, provides a mechanism for the development of MS in people infected by EBV.
Both studies add weight to the hypothesis that EBV causes MS. For Dr. Ascherio, the Harvard study proves that EBV drives MS, even if more work is needed to find out why only a fraction of infections result in MS. According to Dr. Ascherio, “We’ve all been brainwashed with the idea that association is not causation. OK, but then give me an alternative explanation for all the data.”
Everyone may not agree with Dr. Ascherio. But all researchers can agree on one thing—MS is a very puzzling disease. My view is that the Harvard and Stanford research groups have provided key pieces of the puzzle. But it appears that one or more additional factors are required to trigger MS. It could be that other long recognized risk factors for developing MS, such as, race, climate, vitamin D levels, genetics, and smoking provide remaining pieces of the puzzle.
Nonetheless, I agree with Dr. Ascherio’s opinion that the findings of his research group represent “a big step because it suggests that most MS cases could be prevented by stopping EBV infection.” While there is no vaccine against EBV at present, several groups are working on developing one. In a perspective that accompanied the Harvard group’s Science paper, Dr. Lawrence Steinman, a MS researcher at Stanford, claimed an experimental mRNA vaccine against EBV is one of a number of approaches being designed to stop the virus from affecting the brain. The question now, he said, is, “Can we make multiple sclerosis go away?”
Is MS no longer idiopathic? Although knowledge is building regarding the pathogenesis of MS, in my opinion it remains an idiopathic disease. The official definition of idiopathic is: “relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown.” The recent evidence from Harvard and Stanford provides the strongest support so far that EBV causes MS, but additional research is needed to unequivocally establish the link.
AIDS is the disease that best demonstrates the potential importance of determining that an infectious agent is the cause of a disease. First recognized in 1981, AIDS was idiopathic until 1984 when its cause, namely, HIV was discovered. Additional proof that HIV causes AIDS was provided when it was shown that antiretroviral drugs not only saved lives but also profoundly inhibited the growth of the causative agent—HIV. Antiviral drugs were then rapidly developed, and a disease that was uniformly fatal became transformed into a chronic disease with a normal life span thanks to the effective drug therapies that are taken for life.
Presently, I believe the evidence supporting a causal link of EBV infection to MS is sufficiently compelling to attract additional major research funding as well as the engagement of the pharmaceutical industry in development of vaccines and drugs that will suppress, if not totally eliminate, EBV infection. If potent anti-EBV agents are developed that can free MS patients of this virus as well as their physical and mental suffering, we’d have proof of a causative role, and more importantly, a tremendous advance for the 2.8 million people worldwide impacted by this serious disease.