AAN 2022 | The molecular basis of EBV triggering multiple sclerosis
Lawrence Steinman, MD, Stanford University, Stanford, CA, comments on the etiology of multiple sclerosis (MS) regarding the Epstein Barr virus (EBV). An estimated 95% of individuals worldwide are infected with EBV, a virus that invades B-cells and persists, usually asymptomatically. A connection between EBV and MS has long been suspected, but newly published data provide the strongest evidence yet that EBV may be the predominant trigger of MS. The longitudinal study of over 10 million US military personnel revealed 995 incident MS cases during the investigation period, of whom all but one individual tested EBV-positive prior to MS symptom onset. Additionally, in those who were originally EBV-negative, a 97% seroconversion rate was seen in individuals who developed MS, compared to 57% of those who did not. Dr Steinman discusses work analyzing the molecular basis of EBV, whereby his team found interesting molecular similarities between one of the components of EBV, Epstein Barr nuclear antigen 1 (EBNA1), and a molecule in the white matter of the brain called glial cell adhesion molecule (GlialCAM). Thus, it is thought that molecular mimicry is one of the leading mechanisms at play here. This interview took place at the American Academy of Neurology 2022 Congress in Seattle, WA.
Transcript (edited for clarity)
EBV infects B-cells. About 95% of us have been infected with EBV. It’s the virus that, among other things, causes mononucleosis. So a big question is if 95% of us have been infected and our B-cells are persistently infected, but the virus remains latent throughout our lives, how could that trigger multiple sclerosis in rare individuals? The point is that we saw a very interesting molecular similarity between one of the components of EBV, a factor called EBNA1, Epstein-Barr nuclear antigen one, and it has a striking molecular identity with a molecule in the white matter of the brain called GlialCAM...
EBV infects B-cells. About 95% of us have been infected with EBV. It’s the virus that, among other things, causes mononucleosis. So a big question is if 95% of us have been infected and our B-cells are persistently infected, but the virus remains latent throughout our lives, how could that trigger multiple sclerosis in rare individuals? The point is that we saw a very interesting molecular similarity between one of the components of EBV, a factor called EBNA1, Epstein-Barr nuclear antigen one, and it has a striking molecular identity with a molecule in the white matter of the brain called GlialCAM. CAM stands for cell adhesion molecule. That’s probably how the immune system gets tricked into, instead of just recognizing something in the virus, it recognizes something that’s in your white matter.
Now the epidemiology side of the story was a 10-year campaign by my colleague, Alberto Ascherio at the Harvard School of Public Health. He showed, with exquisite epidemiology on an enormous sample from the US military, that everyone with MS is infected with EBV, and that of the people who entered the military and were EBV negative, 34 out of 35 who went on to develop MS converted from negative to positive. It was a confluence of work in two labs, done independently. One, a brilliant epidemiological effort, and then what my colleagues and I did at Stanford looking at a molecular basis.
It’s very interesting that there are other molecular mimics of EBNA1 that are located to neighboring regions of EBNA1. I’m hosting a colleague from the Karolinska and the Karolinska reported another molecule called anoctamin, and anoctamin and GlialCAM are very interesting because they both are involved with calcium signaling in the brain, so there’s a lot to learn.
The implications of all of this is, could we make MS go away with an effective vaccine to EBV. Maybe. Will antivirals work to make MS a much more benign disease or make it go away? That needs to be checked. And then would we be able to simply tell the immune system, don’t attack the GlialCAM mimic and there’s technologies for that. So, I don’t think it will happen tomorrow. I don’t think it will happen as fast as we got COVID vaccines, but I think that we may be able, a generation from now, to say there used to be a disease called multiple sclerosis. That would be pretty cool. It happened for polio, so why not for MS.
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Disclosures
Dr Steinman consults for TGTx.
