EBV and Multiple Sclerosis: More of the Story

 by Derek Lowe

I wrote a year ago about evidence for a connection between Epstein-Barr virus (EBV) and multiple sclerosis. Since then, I’m glad to report that the evidence has become even stronger.

The first new advance was the discovery of a region of an EBV protein (EBNA1) that could well be the site of the problem. Antibodies that are raised to the 386-405 part of the EBNA1 protein also recognize a particular epitope (amino acids 370-385) of a protein in human glial cells. This GlialCAM protein seems to be essential for glial cells to perform one of their key functions, producing and maintaining the myelin sheath around neurons, and demyelination is the exact defect that is seen in MS. If you infuse such antibodies into normal mice, they come with MS-like symptoms and nerve damage. In addition, this team found that CD8+ T cells from MS patients that recognize EBNA1 also recognize GlialCAM, while EBNA1-recognizing T cells from control patients are more selective and don’t bind GlialCAM. (That same protein, by the way, is also of interest in glioblastoma).

Coupled with the epidemiology noted earlier (see the earlier blog post linked above), this is very strong evidence for the hypothesis. But the huge majority of people who are infected with EBV (almost everyone is!) don’t develop MS. Fine, you might say, that’s because they don’t develop those particular antibodies to the EBNA1 epitope, the ones that seem to be causing all the trouble. Unfortunately for that explanation, there are indeed people who have been infected with EBV, and who develop those exact antibodies in response, and who still don’t develop multiple sclerosis.

An explanation for that might now be at hand. This new paper shows that this autoreactivity is subject to several controls of its own, and that these can vary widely between individuals. Other cell-destroying components of the immune system (NK “natural killer” cells) appear to eliminate the B cells that are turning out the autoreactive antibodies. There really need to be some feedback mechanisms like this in the system, because autoreactivity of your own tissues to your own immune system is both bad news and not all that uncommmon, either. And the authors also show that whether or not these B cells survive being culled depends on HLA-E expression, a key mediator for recognition by the patrolling NK cells, which itself depends on several other variable factors. Taken together, they calculate that individuals who have the B cells expressing the glial-targeting antibodies can have their risks for MS vary by up to 250-fold, depending on how HLA-E expression lines up.

So if this holds up, then the etiology of MS would go like this: first, a person is infected with the Epstein-Barr virus (and that’s a large percentage of the population). Second, that person’s immune response features clonal expansion of antibodies towards a particular epitope of the EBNA1 viral protein, which cross-reacts with the GlialCAM protein on the surface of glial cells in the nervous system. I’m not sure what proportion of EBV-infected people express these, but this eventually leads to demyelination and immune cell infiltration into the nervous tissue, the hallmarks of the MS disease state. There is also a T-cell population that has this same cross-reactivity problem. And finally, the patient apparently must also have an insufficient B-cell quality control response to the cells that are producing these antibodies, with not enough of them being attacked by NK cells and destroyed. The T cells mentioned above that have a selectivity problem of their own might be getting their antigen presentation from the same pathways that produce those B cells; I don’t know if that’s clear yet.

This whole story is turning into a classic of modern immunology. There are still some details to be worked out, but a lot of strong evidence is coming together. That of course leads to thoughts of disease prevention, and it will be very interesting to watch the progress of the (several) vaccine candidates against EBV. Now that we know more about what to look for, we should be able to monitor what the immunological state is after vaccination and what the effect might be on prevention of MS.

A key issue is when a person becomes infected with EBV. The epidemiological study indicated that the risk of developing MS is much higher in people who are infected only after reaching adulthood as opposed to infancy, and there’s still a lot of work to be done to understand what leads to this (and where a vaccinated patient will land on that scale). The hope is that infant vaccination could cause multiple sclerosis to outright disappear as a disease, but it’s also possible that other factors could partially cancel that out or possibly even make things worse. But we’re getting the tools to find that out - we’ve never had them before.

https://www.science.org/content/blog-post/ebv-and-multiple-sclerosis-more-story