Does a virus cause multiple sclerosis?
It has long been speculated that viruses are the root cause of multiple sclerosis (MS). The main suspect is Epstein-Barr virus (EBV), which causes infectious mononucleosis (“mono”). EBV is one of the Big Three when people talk about environmental factors and MS; the other two are sun exposure/vitamin D and cigarette smoking (Ascherio & Munger. Semin Neurol 2008;28:17-28).
So how could a virus “cause” MS?
Viruses became the focus of attention for several reasons. Some are known to live inside neurons. One example is varicella zoster virus, which causes chickenpox. After your chickenpox clears up, the virus remains dormant inside nerves. It causes painful shingles if it reactivates. Other viruses are known to target specific cells in the central nervous system. Of particular importance is JC virus, which can infect the cells that produce myelin (the oligodendrocytes) and cause demyelination. The JC virus can reactivate if the immune response is impaired. This used to occur primarily in people after an organ transplantation or if people infected with HIV/AIDS. Now it’s seen in people with MS or other autoimmune diseases during treatment with Tysabri or other treatments of that type.
EBV first made its appearance as a possible cause or trigger of MS back in the 1970s (Sumaya and colleagues. Trans Am Neurol Assoc 1976;101:300-302). Viruses were a hot topic in the 1970s and early 1980s (think of herpes and HIV). In fact, the possible link between MS and viruses prompted researchers to study interferons (so-called because they interfere with virus) as an MS treatment.
Viruses seemed to explain why MS was more common in some parts of the world. One theory was that people who are exposed to more diseases in childhood develop a better immune response to a wide range of bugs. According to this “hygiene hypothesis”, people in westernized countries – who benefit from better sanitation and less exposure to diseases – encounter EBV at a later age and their immune system doesn’t respond as well.
In support of this is the finding that people infected with EBV as adolescents or adults are about three times more likely to develop MS compared to people infected with EBV during childhood (Ascherio & Munger. Ann Neurol 2007;61:288-299). People never exposed to EBV were 10-fold less likely to develop MS.
Genetics gets factored into this theory as well: the people who are at risk are those with a genetic predisposition to develop MS because they have what has been called “a general aberration of the immunological system (Sumaya and colleagues. Arch Neurol 1980;37:94-96). Several genes involved in how the immune system processes foreign proteins (such as components of viruses) have been implicated in MS.
A related phenomenon is called “molecular mimicry”. What this means is that some viral proteins resemble the protein sequences that make up myelin. The immune system learns to recognize the virus, then is tricked into attacking myelin as well. This could occur without a genetic predisposition to MS (which could suggest that EBV is the cause of MS); or may be because the immune response in people with the “MS gene” is more likely to make this mistake (so EBV might be a trigger for an underlying problem).
Molecular mimicry may also play a part in a common problem seen in MS: a viral infection triggering a relapse. One study found that there was a three-fold higher risk of having a relapse in the two weeks before an infection or in the five weeks after an infection (Correale and colleagues. Neurology 2006;67:652-659). These were true relapses because an increase in MS activity was also seen on MRI. Viral infection also appeared to stimulate immune cells (T cells) that targeted myelin.
Of course a viral infection such as the flu is not the same bug as EBV. So it would have to be presumed that components of both types of virus resembled myelin. Or it could be that a specific problem in the immune response (possibly due to genetics) resulted in the same error. Or it may be an immune problem that begins with EBV, and later viral infections add insult to injury.
One challenge in teasing out the possible role of EBV in MS is that most people – with or without MS – have been exposed to it at some point during their lives. A recent study found that EBV exposure was detectable (by the presence of antibodies to EBV) in about 98% of people with MS, and 92% of people without MS (Almohmeed and colleagues. PLoS One 2013;8:e61110). One difference, however, may be in how robust the immune response is to EBV. Antibody levels are much higher in people with MS compared to people without MS, and this spike in antibody levels appears to occur after age 25 (DeLorenze and colleagues. Arch Neurol 2006;63:839-844; Levin and colleagues. JAMA 2005;293:2496-2500). So this may be an early warning sign of MS. The suggestion is that after age 25, something changes in how the immune system responds to EBV – just before MS is diagnosed (Sundstrom and colleagues. Neurology 2004;62:2277-2282). What this change is, and why it occurs then, are a mystery.
These observations suggest that EBV is indeed a trigger for MS. What needs to be determined is if antibody levels of other viruses also increase just before the onset of MS. In other words, do many different viruses (not just EBV) unmask a hidden problem in the immune response? And why does this lead to a cascade of events – inflammation, demyelination – that are the hallmarks of MS?
There are many unanswered questions. At the moment, it appears that EBV may be the best mimic, tricking a susceptible immune system into launching an attack on myelin. The body then tries to limit the damage with an inflammatory response which just makes things worse. If this series of events proves correct, it underscores the importance of taking an MS medication as early as possible to put out the fires that EBV has lit.
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