April 16, 2003
By Christine Haran
Viruses that linger in the body long after the symptoms of an infection subside have been linked to a number of different diseases and conditions. It's well known, for example, that the Epstein-Barr virus, or EBV, causes infectious mononucleosis, a disease that is often acquired during adolescence.
But few people realize that this common virus has also been linked to some cancers, and, recently, multiple sclerosis. MS is a chronic, progressive disease of the central nervous system, with a wide range of symptoms that typically come and go over time.
MS, which is primarily diagnosed in young adults, is classified as an autoimmune disease. In MS, cells of the immune system mistakenly attack myelin, a coating that surrounds nerves in the brain and spinal cord. When this protective coating is damaged, messages cannot be transmitted properly between the brain and the spinal cord and the rest of the body.
Confirming that EBV increases risk for MS would provide researchers with a better understanding of the disease. Dr. Alberto Ascherio, an associate professor of nutrition and epidemiology at the Harvard School of Public Health, is one researcher who has recently highlighted the potential link between EBV and MS. He is the senior author of a study, conducted with the Walter Reed Army Institute of Research, and published in the March 26th issue of The Journal of the American Medical Association.
In the study, Ascherio and his colleagues analyzed blood samples of people who later developed MS and those of people who did not develop the disease. The blood samples were analyzed for anti-EBV antibodies. Antibodies are produced by the immune system in response to viral infections and their presence in the blood attests to a presence of a viral infection.
Ascherio found that the risk of developing MS for individuals with the highest levels of the anti-EBV antibodies was 30 times higher than those of individuals with the lowest levels.
Below, Ascherio explains EBV and its potential link to MS and other conditions, as well as how such a link could affect MS prevention and treatment.
What is the Epstein-Barr virus and how prevalent is it?
EBV is a ubiquitous virus mostly transmitted through saliva, which infects about 95 percent of the adult population in the United States. When the virus infects children it usually doesn't cause any symptoms. But when people are infected during the adolescence or adulthood, it can cause infectious mononucleosis.
Is EBV a risk factor for cancers?
The association is well established for Burkitt lymphoma, a cancer that is seen most commonly in some parts of Africa, and for nasopharyngeal carcinoma, which is common in Asia. Virtually all the cases of these diseases in this region are related to EBV. The relationship with Hodgkin's disease is more speculative: Some cases of Hodgkin's disease are EBV positive and others are EBV negative.
Why did you decide to investigate a potential link to multiple sclerosis (MS)?
The geographical and age distribution of infectious mononucleosis and MS are very similar. It was noted more than 20 years ago that both diseases are rare in the equatorial and tropical region; the incidence increases when you get it to higher latitude. EBV and MS also tend to affect the same population group: Caucasians are at higher risk than people of Asian or African descent. And both diseases occur at slightly younger age in women than in men.
So all these similarities supported an investigation. The original hypothesis was that MS could be sort of a rare reaction to EBV, specifically when the EBV infection occurs later in life. People who have a history of infectious mononucleosis have been found to have a three- or fourfold increase in risk of MS.
What did you find when you looked at the Nurses' Health Studies for a link between MS and EBV?
We took advantage of two large studies, the Nurses' Health Studies, which followed more than 200,000 women for many years. We looked at the blood samples collected before the onset of MS in women who developed MS and compared the antibody titers, or the amount of anti-EBV antibodies in the blood, to women of the same age who did not develop MS.
We found a strong association between the antibody levels and the risk of developing MS. But MS is a relatively rare disease so there weren't many samples in these large studies. We had only 18 women in that study with blood collected before MS onset. But in spite of the small number of cases, we found a strong, significant association between EBV and MS.
Did this new study involve more participants?
Yes, the Department of Defense keeps these amazing facility where they have blood samples from more than 3 million Army personnel. So we were able to find out which people in that population developed MS over the years and then to go back and retrieve their stored blood samples.
These study results went beyond our original results in several ways. One important thing we looked at was the length of the interval between the blood collection and the onset of neurological symptoms. In the Nurses' Health Studies, the interval was relatively short, generally less than two years. So in those situations, you cannot exclude the possibility that the elevated antibody levels among women who will develop MS would, in fact, just be an early sign of MS.
But we were interested to see how long before the onset of neurological symptoms you could see a significant elevation in anti-EBV antibodies. And in this study, we had enough numbers and a long follow-up; the overall interval was an average of four years, but we did analysis with blood collected five to 10 years before. And we found the same strong association: High levels of these antibodies measured in blood in healthy young adults may predict a 30-fold increase in risk of MS five to 10 years later. This clearly indicates that the elevation in anti-EBV antibodies is very unlikely to be a consequence of MS.
Why might EBV cause MS?
At this point we can only speculate, but the prevailing hypothesis would be that the immune response to EBV may include immune cells or antibodies that may cross-react with some protein in the body. In some people, who are probably genetically predisposed, the immune cells that are meant to recognize EBV, and to control EBV infection, happen to also recognize some protein in the myelin and/or in the brain and cause damage. But there is no direct proof that this is true. So this is something that needs to be investigated.
What kind of studies and information do you need to confirm your findings?
When trying to establish causality between an infectious agent and a complex disease, it's not as straightforward to design a study as it could seem because we are not looking at a one-to-one relationship as is the case with simple infectious diseases. If you are infected by the measles virus, for example, you get the measles. What we are looking at here is a complex cascade of genetic and environmental factors that are possibly interacting. And the fact that the EBV is ubiquitous has made this more difficult.
We would like to see if there are interactions between the EBV infection and an individual's genetic background. But more compellingly, people should start looking at immune cells in people with MS and see if the immune cells that regulate EBV infections are different in number or reactivity among people with MS than people without MS.
Could this potentially lead to different kinds of immunotherapies for MS?
If we find that the virus plays an important role in MS, it will open
up a new area for drug research that may include antiviral drugs. Because
today, the anti-virus drugs that are available are not very effective against
EBV. It could also help to identify more precisely what type of immune
cells or antibodies may be involved in causing MS. And, of course, a vaccine
remains a possibility. If it turns out that MS and EBV are causally related,
then a vaccine that prevents or reduces EBV infection could have a role
in preventing MS as well.
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