Antibodies to the EBNA1 protein of Epstein-Barr virus (EBV) can cross-react with glial cell adhesion molecule (GlialCAM), a component of the myelin sheath.

The findings are the first to report a mechanism for how viral infections can cause autoimmune disorders. And somewhat ironically, they were reported by a former skeptic.

"Three years ago, I was extremely dismissive of EBV" as a cause of multiple sclerosis (MS), William Robinson told BioWorld Science.

Robinson, who is a professor of immunology and rheumatology at Stanford University, had several reasons for his skepticism.

For one thing, there are multiple purported viral triggers for autoimmune disorders including MS, rheumatoid arthritis and systemic lupus erythematosus (lupus). But with the exception of Coxsackievirus, which can trigger type 1 diabetes through inflammation and tissue damage, a mechanistic explanation for how the supposed trigger might cause autoimmunity has been sorely lacking.

And while 99% of patients with MS are infected with EBV, so are 94% of adults without.

In their studies, which were published online in Nature on January 24, 2022, the team investigated the binding repertoires of B cells from patients with MS. The disease can be treated via the depletion of antibody-producing B cells, but it had been unclear to date which antibodies, specifically, were causing trouble in MS.

Robinson's lab has developed a B-cell repertoire sequencing technology, he explained. "That ability to sequence the B-cell repertoire and then generate monoclonals expressed by the individual B cell – that's how we made this discovery."

The team first showed that antibodies from the cerebrospinal fluid (CSF) of MS patients bound to the brain tissue of animals with experimental autoimmune encephalitis, the closest animal model of MS, but not to brain tissue from healthy animals.

"And then we put them on herpesvirus, and lo and behold, EBV bound," Robinson said. "At picomolar affinity."

The team went on to show that about 25% of MS patients had antibodies to a specific part of the viral EBNA1 protein, amino acids 365-425. Those antibodies cross-reacted with GlialCAM, which is expressed by cells of the myelin sheath that enables high-speed neuronal communication and is damaged in MS.

Cross-reactive antibodies could play a role in more than the 25% of patients where they were present at the time of sequencing. The antibody repertoire can change over time, and it is possible that the initial attack of GlialCAM leads to other antibodies that attack other parts of the myelin sheath, in a process called epitope spreading.

The findings come shortly after a team led by Alberto Ascherio from the Harvard School of Public Health used a database of nearly 10 million members of the U.S. military to demonstrate a causal link between EBV and MS. That paper, Robinson said, was "compelling," as far as demonstrating causality, "but there's no mechanism. What our paper shows is that there is molecular mimicry -- EBV is mimicking a protein in glial cells in the brain."

That mechanism is a "key element for showing that they are linked not just epidemiologically, as the Ascherio group did, but mechanistically."

Why it is only the unlucky few who develop MS after EBV infection remains an open question. It is possible that an individual's major histocompatibility complexes (MHCs) play a role. Alternately, some strains of EBV but not others raise the risk for certain cancers, and the same may be true of MS.

Therapeutically, the work suggests that antivirals clearing EBV might prevent the progression to MS, or possibly treat existing cases.

Whether such treatment would be effective, though, needs to be tested empirically.

If the cross-reactive antibodies Robinson and his colleagues have identified are "a molecular hit-and-run," he said, "then maybe the horse is out of the barn."

Long term, prevention through an EBV vaccine may be the best way to tackle MS. But as Robinson pointed out, "we all get EBV when we're in high school."

The virus is transmitted through saliva, leading to the moniker "kissing disease" for mononucleosis, which is another consequence of EBV infection.

MS can be diagnosed decades after the original exposure to EBV, Robinson said. So "even if we had a vaccine today, it's not going to solve the MS problem until 30 or 50 years from now."