Does an infection cause MS?
A new study claims that a common infection can cause multiple sclerosis in susceptible people (Bjornevik et al. Science 2022;375:296-301). The implication is that preventing this infection would eliminate the development of new cases of MS. However, while the results are exciting, it is a little premature to say that the cause of MS has definitively been identified.
The study used blood samples from the U.S. Department of Defense serum repository collected from 1993 to 2013. As part of its HIV screening program, DoD routinely obtains blood from all military personnel when they join and every two years thereafter. The researchers then identified 801 people who later developed MS and compared them to 1,566 people without MS. Antibody testing showed who had been infected with Epstein-Barr virus (EBV).
EBV is a type of herpesvirus. It was first identified as the cause of a rare type of cancer, but it is better known as the cause of infectious mononucleosis – called the kissing disease because the virus is transmitted by saliva. Like other herpesviruses, EBV is never eliminated from the body; after infection it hides out in a type of immune cell called a B cell. Many people become infected in childhood but remain unaware of it because EBV infection is typically associated with no or only mild symptoms. If EBV is acquired during adolescence, there is a higher risk of developing mononucleosis. By the late teens, a U.S. survey found that 90% of people were infected with EBV (Balfour and colleagues. J Infect Dis 2013;207:80-88).
In the new study, only 1 of the 801 people who developed MS had not been exposed to EBV (called seronegative). In the subgroup of 35 people with MS who were seronegative at the start of the study, 34 later became infected with EBV. In all cases, EBV infection occurred prior to the development of MS. This translated to a risk of developing MS that was 32 times higher for people with EBV infection compared to those without infection.
These results indicate that EBV infection is a major risk factor for developing MS. But taken alone they do not show the EBV causes MS. It could be a matter of reverse causation, which means that some unknown factor predisposing a person to develop MS may also predispose them to becoming infected with EBV. In fact, in the group of people who were seronegative at the start, those who later developed MS were almost twice as likely to become infected compared to those who did not develop MS.
What distinguished this study from previous ones is that the researchers also looked at a type of protein (called neurofilament) that appears when nerve cells become damaged. People with MS have higher neurofilament levels because of ongoing tissue damage; levels increase during a relapse and decrease during treatment with most disease-modifying therapies (Disanto and colleagues. Ann Neurol 2017;81:857-870).
The study found that neurofilament levels were comparable in healthy people and those who would later develop MS. However, after EBV infection, neurofilament levels increased only in people who later developed MS. The authors concluded that the disease process of nerve damage that is characteristic of MS only begins once a person has become infected with EBV. This implies that the MS-related damage would not have occurred without EBV infection.
These findings strongly suggest that EBV is the trigger that initiates the MS disease process. The study has a number of limitations, however, so it is premature to say that EBV is the definitive cause of MS. More studies will be needed. And as good research tends to do, it raises more questions than it answers. If EBV is the trigger and 90% of people are infected, why does it cause MS in only a minority of people? Does a person’s age at the time of infection matter? How does EBV cause an autoimmune response in some people? What other circumstances – such as genetics or environmental factors (smoking, low vitamin D) – are needed to start the disease process that culminates in MS?
If EBV infection is truly a necessary precondition for developing MS, this could lead to many exciting developments in MS treatment. An EBV vaccine could potentially prevent people from developing MS. Thus far, vaccination has been shown to prevent mononucleosis but not EBV infection (Sokal and colleagues. J Infect Dis 2007;196:1749-1753). Other EBV vaccines are now in development and could be available for clinical trials very soon. If it could be shown that preventing EBV infection with vaccination also prevented MS, it would definitively prove that EBV is the cause of MS.
For people with MS, a number of new treatment options could become available. Antiviral drugs have already shown some benefit in MS (Lycke and colleagues. J Neurol 1996;243:214-224. Bech and colleagues. Neurology 2002;58:31-36). But these drugs don’t kill EBV that is lying dormant in cells. Antiviral drugs with different targets would be needed.
A person’s own immune cells (called T cells) could be trained to attack the B cells that are infected with EBV. If used early, this might prevent some of the disability that occurs later on. At least one such T cell therapy is currently in development (Pender et al. JCI Insight 2018;3:e124714).
A number of current MS treatments, such as Ocrevus, Kesimpta, Lemtrada and Mavenclad, potently reduce the number B cells. An intriguing suggestion is that part of their efficacy may be due to eliminating EBV-infected B cells. So we may see these drugs (or other drugs) get a makeover so that they eliminate only EBV-infected B cells. Alternatively, a future treatment regimen might include an antiviral add-on therapy to increase the benefit of therapy.
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