Evidence is mounting that a garden variety virus that sometimes causes mono in adolescents is the underlying cause of multiple sclerosis, a rare neurological disease in which the immune system attacks the brain and spinal cord, removing the protective insulation around nerve cells, called myelin.
It is still unclear exactly how the virus – Epstein-Barr virus (EBV) – can trigger MS and why MS develops in a tiny fraction of people. About 95% of adults have been infected with EBV, which often strikes in childhood. MS, on the other hand, often develops between the ages of 20 and 40 and is thought to affect about a million people in the USA. Yet years of evidence have consistently pointed to links between the childhood virus and chronic demyelinating disease later in life.
With a study published today in Science, the link is stronger than ever, and outside experts say the new findings offer further ‘compelling’ evidence that EBV is not just linked to MS; it is an essential trigger of the disease. The study found, among other things, that people had a 32 times higher risk of developing MS following an EBV infection in early adulthood.
“It’s a great article,” Dr Ruth Dobson, professor of preventive neurology and MS expert at Queen Mary University of London, told Ars in an interview. “The evidence adds up and adds up and adds up…While we don’t understand biologically how EBV drives MS and we’re thinking about theories of causation, we really have the rest of the building blocks in place” , said Dobson, who was not involved in the new scientific study. “This is another piece of evidence that really supports this theory” that EBV triggers MS.
For the study, researchers led by Harvard neuroepidemiologist Dr. Kjetil Bjornevik extracted an exceptionally rich repository of blood serum samples collected from a cohort of more than 10 million active duty military personnel between 1993 and 1993. 2013. Samples were taken from relatively healthy, fit, and young servicemen as part of standard screenings for infections, including HIV.
In the cohort, there were 801 members who developed MS and had banked up to three serum samples before their diagnosis. This gave researchers the unique opportunity to go back in time and examine serum samples from MS patients years before they developed the disease. The researchers were also able to compare samples from 801 MS patients with samples from 1,566 cohort members who did not develop MS and could serve as controls.
Of the 801 people who developed MS, all but one had antibodies indicating EBV infection when they were diagnosed with MS. And most of these EBV infections occurred earlier in life. At the start of the 20-year period, only 35 of 801 MS patients were initially negative for EBV. At the end of the period, 34 of these 35 had developed anti-EBV antibodies, ie seroconverted, before their diagnosis.
Bjornevik and his colleagues compared these 35 initially EBV-negative staff members with 107 control group members who also initially tested negative. They found that the rate of seroconversion in the 35 who would develop MS was significantly higher than the rate in the control group: 97% of the 35 seroconverted before diagnosis, while only 57% of the control group seroconverted within 20 – period of the year. From these data, the researchers calculated that people who seroconverted had a 32 times higher risk of developing MS.
It is not known why the one MS patient did not appear to seroconvert during the study. The authors speculate that, given the gaps in sampling, it is possible that the person has seroconverted between the last sample and the diagnosis. It is also possible that the person was misdiagnosed with MS or was infected with EBV, but for some reason did not seroconvert. It is also possible that the person had a rare type of MS triggered by something other than EBV. Regardless, the authors felt that the single isolated case did not weaken the strong link between MS and EBV.
But EBV was not the only virus examined by the researchers. In fact, they screened serum samples for antibodies targeting more than 200 viruses. Screening indicated that the risk of MS did not increase after infection with a virus other than EBV. Additionally, when the researchers compared the overall antiviral antibody responses in the MS patients to those in the controls, they found that the overall antibody responses were similar. This suggests that there was not some sort of underlying immune dysregulation that spurred the development of MS after EBV infection.
Overall, the study adds to a slew of other data linking EBV to MS. Similar to the new study, other research has found a two- to three-fold increase in the risk of developing MS after an episode of infectious (“mono”) mononucleosis, which is caused by EBV. The virus specifically attacks a type of immune cell called B cells, and after the initial infection the virus remains dormant in these cells for the rest of a person’s life. Several studies have found EBV-infected B cells in the brain and demyelinated lesions in MS patients. MS patients also sometimes have high levels of specific anti-EBV antibodies that target proteins called EBV nuclear antigens. And, currently, one of the most effective treatments for MS is antibody therapy that targets circulating memory B cells, which harbor dormant EBV.
“There has been a lot of evidence to suggest that EBV plays a role in MS,” Bjornevik told Ars. “We believe that with this study we provide compelling evidence that there is in fact a causal relationship between EBV and MS…We believe this is a big step forward and is the ultimate proof. more convincing to date.
Dobson and other experts agreed. In an email to Ars, Dr. Helen Tremlett, a neuroepidemiologist and MS expert at the University of British Columbia, called it an “important study” that “provides credible evidence of the relationship between exposure to EBV and the risk of MS”. Tremlett was not involved in the new study but noted that she had collaborated with some of the co-authors in the past.
In an accompanying perspective article in Science, Stanford MS expert William Robinson and neurologist Lawrence Steinman wrote that the results “provide compelling data implicating EBV as a trigger for the development of MS.”