The cause of multiple sclerosis, a progressive neurodegenerative disease that affects nearly 3 million people worldwide, has remained unclear despite decades of research. Now, research published today (January 13) in Science bolsters the case that one of the chief suspects—Epstein-Barr virus (EBV), a common cause of mononucleosis—can also trigger MS.
The research team examined the correlation between Epstein-Barr virus infection and MS in by analyzing serum samples and medical data collected from a cohort of more than 10 million US military service members, finding that EBV infections increased the odds of an MS diagnosis during their service by more than 32-fold. No such increases in likelihood were found for other viral infections. The researchers also found that, when they looked retrospectively at samples from the cohort members that were eventually diagnosed with MS, a biomarker for neurodegeneration became elevated only after EBV was detectable in their blood.
Lead author and Harvard T. H. Chan School of Public Health epidemiologist Alberto Ascherio tells The Harvard Gazette that “this is the first study providing compelling evidence of causality.” He adds: “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”
MS is characterized by scarring of the brain, the result of chronic autoimmune inflammation causing the demyelination of neurons, explains STAT. What exactly triggers the immune system to launch this self-directed attack has remained unclear, though viruses have been at the top of the list of potential culprits for decades. In particular, herpesviruses emerged early on as primary suspects because of their propensity for chronic infections. However, none of the numerous studies linking herpesvirus to MS could provide strong evidence that infections were causing the disease.
Conclusively linking Epstein-Barr to MS has proven especially challenging because of the timing of both diseases: EBV infections often happen in childhood or young adulthood, roughly a decade before MS symptoms appear, according to the Gazette. But the researchers say they were able to overcome this hurdle thanks to the immense dataset they used: the Department of Defense Serum Repository, a trove of roughly 62 million serum samples that were collected from more than 10 million US service members every few years during their tenure in the military, along with medical information about the serum donors.
The team was able to use the temporal resolution of the repository to dig deeper into the timing of EBV infection and MS development. In addition to correlating MS diagnoses with prior EBV infection, the team found that an increase in serum levels of neurofilament light chain (NfL)—a biomarker of neurodegeneration that previous research suggests becomes elevated a couple years before MS symptoms appear—occurred only after EBV antibodies also increased.
“Not only were soldiers not diagnosed with MS at the beginning of the study, but their NfL levels were also negligible, so they probably didn’t have a case of MS smoldering under the radar,” University of California, San Francisco, neurologist Michael Wilson notes to STAT, which he says adds weight to the idea of causality.
Some experts remain skeptical that the virus directly causes MS. Anthony Reder, a multiple sclerosis expert at the University of Chicago who was not involved in the work, suggests to The New York Times that the immune response to the virus, rather than the virus itself, may ultimately be to blame, noting that MS patients have overactive immune systems in general. The authors attempted to exclude this possibility by comparing cytomegalovirus infection, another common viral infection, with EBV. Increases in serum levels of cytomegalovirus antibodies did not predict NfL levels, they found. But Reder cautions that cytomegalovirus may be a poor choice for comparison, as some previous studies have found infections with it to be oddly protective against MS.
Another thing that remains to be explained is why MS is so rare, given that EBV infection is so common, Rocky Mountain MS Center neurologist John Corboy tells STAT via email. Approximately 95 percent of adults have been infected by the virus, according to the Gazette, but MS is seen in less than half a percent. In general, the study “leaves many questions about pathogenesis unanswered,” Corboy writes.
Still, “It really is the most convincing data we’ve had for a causal association,” Michael David Kornberg, a multiple sclerosis specialist at Johns Hopkins University, tells the Times.