Even More on Multiple Sclerosis and EBV

 by Derek Lowe

The updates to things I've been writing about here are coming almost too quickly to catch up with, especially since I try to vary the subject matter here day by day (on the theory that if someone stops by and finds that they're not interested in today's post, that they have a good chance of finding something totally different the next time). But early this week I was writing on the latest developments in the developing story of whether multiple sclerosis (MS) is a consequence of infection by Epstein-Barr virus (EBV), and there have been more publications bearing on this already.

I had mentioned in Monday's post that one of the pieces of the puzzle seems to be that while almost everyone gets infected with EBV at some point (and that timing probably matters), obviously not everyone goes on to an immune attack on their own nervous system. There's a particular class of antibody that can be raised to a particular EBV protein, though, that can cross-react to an important protein on the surface of glial cells, and that's the connection. But in a good number of cases where that starts happening, the immune system does a last-ditch edit and tries to take out the B cells that are producing these autoreactive antibodies - and the efficiency of that process is another big determinant of someone's risk for developing MS. 

Now this paper shores up that idea, showing that indeed, if you look at the cerebrospinal fluid of MS patients, there's a lot to learn from the T cells found there. 13% of them are targeting B cells which seem to be infected with EBV. This fact has been known for some time, as part of a general association between EBV and MS, but as usual, it's difficult to sort out chickens and eggs. Does having MS make you more vulnerable to Epstein-Barr infection, or does Epstein-Barr make you more vulnerable to MS? The scales are very much tipping toward the latter. This new paper shows that if you dig deeper into that T cell population and look at the lines that have been expanded the most, the proportion of the ones that are targeting those EBV-tinged B cells is still higher (47%). That's a strong clue that this is part of the real pathology of the disease, and as the authors note, there are several possible explanations: perhaps the T cells are just there because they're targeting B cells that are straight-out infected with EBV. Or they may be going after another protein, human or viral, that cross-reacts with one or more human proteins. They could also just be recruited into the nervous system as general consequence of inflammation, making them more of a consequence of the disease rather than part of its cause. But the work I wrote about earlier this week argues that a big part of the MS story is an autoimmune war between T-cell and B-cell populations over cross-recognition of EBV and glial cell proteins, and this lands right into that framework.

Another suprising bit of the story comes from the distant past. This Nature article is an overview of a series of data-rich genomics papers the journal has recently published. These are part of a big push in recent years to unravel the prehistory of Europe and Asia through genomic markers and sequencing of ancient remains, work which is bringing that era into focus in a way that nothing else could do. It's become clearer that there were at least three distinct waves of migration into Europe from Eurasia starting about 45,000 years ago (give or take a few thousand). First there were hunter-gatherers from Asia (who encountered Neaderthals and such on arrival), followed by farming cultures from the Middle East about 11,000 years ago, who were then overlaid by a third wave of animal herders from the eastern steppes about 5,000 years back. It's a complex story that integrates both genomic and archaeological evidence, and you may be wondering what the heck it has to do with multiple sclerosis.

Well, this latest work suggests that genes that are known to confer increased risk for MS actually expanded during this period, and that this (and other genomic signatures) are not (or certainly not all) due to these populations mixing and adapting over the years. Instead, different waves tended to go to different parts of Europe and more or less take over (Denmark, in particular, seems to have gone through some population changes so complete and drastic that genocidal conquest comes to mind as a likely explanation). The MS susceptibility genes came in with that last wave of pastoralist herders, and then became even more common in the northern regions where they settled. This suggests that there was some selection pressure amplifying a favorable trait, which means that there could be some immune advantage here that we aren't appreciating. In addition, I would think that many cases of MS may not strike hard enough and early enough to have a strong effect on sexual selection and childbearing, allowing whatever benefits there are to these immune responses (perhaps more resistance to viruses derived from the domesticated animals?) to outweigh the downsides even more, evolutionarily.

It's an active field, for sure! And the next few years should seen even more puzzle pieces falling into place. I'm glad to be able to witness it all in real time.

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