Link Strengthened Between MS and Epstein-Barr

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Link Strengthened Between MS and Epstein-Barr

Antibodies to Epstein-Barr Elevated Several Years Before MS Onset

 

For Alberto Ascherio, who studies the epidemiology of multiple

sclerosis in relation to the Epstein-Barr virus (EBV), the most

compelling evidence that EBV has an association with MS lies in

those who are uninfected. " Something like 95 percent of us are

infected with EBV, but what about the remaining 5 percent? Their

risk of MS is one thirteenth that of those who are EBV-positive.

They are virtually resistant. "

 

 

 

Kassandra Munger and Alberto Ascherio analyzed data from blood

samples collected from enlisted soldiers to discover a link between

antibodies to Epstein-Barr virus and multiple sclerosis. (Photo by

Steve Gilbert)

 

 

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Because there are so few people who are uninfected with the virus,

this conclusion has been difficult to prove. Ascherio, an associate

professor of nutrition and epidemiology at HSPH and an HMS associate

professor of medicine at Brigham and Women's Hospital, reached it

through a meta-analysis of studies of 100 or so patients, which

translates into only a few uninfected persons per study. Statistical

significance in any one study was difficult to achieve, but

collectively the results were highly significant. To learn more

about Epstein-Barr and MS, Ascherio turned to antibody titers, and

in the March 26 Journal of the American Medical Association, he and

colleagues at the Walter Reed Army Institute of Research report the

results of their study, that antibodies to EBV are elevated in MS

patients even several years before the visible onset of the disease.

" The early increase in the biomarker suggests that it is related to

the pathological process in a way that may help us to elucidate the

etiology of the disease. "

--Alberto Ascherio

 

The idea that a virus may have some role in multiple sclerosis has

endured great shifts in popularity; currently, it is out of favor.

The most commonly envisioned scenario for microbial involvement is

one that is invoked for many suspected autoimmune diseases, such as

type 1 diabetes and Lyme disease, that is, a normal body protein is

confused by the immune system with an antigen of an invading virus

and this mix-up results in an attack on the body's own tissues.

 

But this explanation has not panned out yet for MS. Not only has a

guilty microorganism not been identified, scientists are not

convinced that MS is an autoimmune disorder. Many scientists believe

that a single virus or bacterium may not be responsible; rather, the

cause may lie in the interaction of several agents with an immune

system that responds in a susceptible way to infections in general.

 

Possible Perps

EBV was suggested as a causal agent in the early 1980s due to the

increased titers of antibodies to EBV in MS patients and the

similarity between the epidemiology of MS and that of infectious

mononucleosis, frequently caused by EBV. Many studies then were

performed in an effort to link MS with a microbial cause. But the

high antibody titers to various viruses in the blood of MS patients

were inconclusive since they could have been the result and not the

cause of MS. " Sometimes they found an elevation against one virus

and sometimes against another, " Ascherio said, " but this didn't seem

to mean very much in terms of the etiology of the disease. EBV was

one of these viruses and was put in the pack with all the others for

this reason. "

Ascherio resurrected the EBV hypothesis when he performed a study on

women involved in the Nurses' Health Study, in which he sought to

show that the increase in EBV antibodies occurred before the onset

of MS. In that study, the women's blood samples were taken an

average of 1.9 years before diagnosis. They did, indeed, have

consistently higher titers of serum antibodies to EBV. But since no

one can say for certain when the disease actually began without

magnetic resonance imaging, the primary diagnostic method for MS, it

is possible that the women already had the disease a year or two

before the appearance of symptoms.

 

In an effort to probe further into the past, Ascherio took advantage

of a unique set of data made available by the U.S. Army. The blood

samples of 3 million soldiers are stored at the Department of

Defense Serum Repository in Silver Spring, Md. These samples are

taken at enlistment and every two years thereafter. In the new

study, Ascherio was able to document the occurrence of MS in this

population and to obtain blood samples collected an average of four

years prior to the first reported symptoms.

 

Again he found that antibody titers to EBV were significantly

elevated in future MS cases compared to controls. Antibodies to the

viral capsid antigen (VCA) and the Epstein-Barr nuclear antigen-1

(EBNA-1) were the most definitive: for individuals in the highest

category of VCA titer, the relative risk for later MS was 20 times

higher than controls, and in the case of EBNA-1, more than 30 times

higher. Titers remained stable up to and after diagnosis of MS.

Titers of antibodies to cytomegalovirus, which also persists in the

body after infection, remained low and unchanged.

 

Cause or Effect?

The implication, of course, is that EBV may be involved in the onset

of the disease. " The early increase in the biomarker suggests that

it is related to the pathological process in a way that may help us

to elucidate the etiology of the disease, " said Ascherio. " For us it

means it's not a result of the progression of the disease. It is

noteworthy that anti-EBV titers strongly predicted the risk of MS

even in blood samples collected between 5 and 10 years before the

onset of symptoms. If the antibody titer was a marker of disease

severity or progression, you would expect that the titer would go up

the closer you got to the clinical manifestation, and even more so

after. "

Yet proving MS is not present even four years before disease onset

is still difficult. " I think this study is interesting, and I think

it's well done. The trouble is you don't really know when the

disease begins without having done MRI scans serially, which is

impossible to do, " said David Hafler, the Jack, Sadie and David

Breakstone professor of neurology at Brigham and Women's, who is

unconnected with the study. " I would agree that this study shows

that EBV should be studied in relation to MS, but as with any

epidemiology, it points to a potential direction which has to be

further understood mechanistically. "

 

Ascherio points out that the results have value even beyond the

possibility of a causal connection between EBV and MS. " You may

argue that there is something going on in the immune system that

five years later may become MS. Still, the fact that these antibody

elevations are the earliest detectable marker of this process is

certainly new and important. It's like cancer; you may say in cancer

the cell mutation that leads to cancer may start 10 or 20 years

before. Yet if you find the biomarker that will tell you your risk

of cancer is 20- or 30-fold higher, that would be a tremendous

advancement, " he said.

 

 

For now, Ascherio has his sights set on more mechanistic

questions. " Our future epidemiological work may include determining

whether individuals with MS are infected with a different strain of

EBV than people without MS, and examining the role of genetic

polymorphisms in modifying the EBV-MS association. Insights may come

from the investigation of the cellular immune response to EBV in

patients with MS. We are planning--in collaboration with others--to

pursue all of the above, " he said.

 

--Jennifer Frazer

http://focus.hms.harvard.edu/2003/April18_2003/epidemiology.html