HERVs and Multiple Sclerosis, part 1

I have a new paper sitting on my desk that I plan to summarise in the near future. The study investigates the relationship between syncytin, a human endogenous retroviral protein, and MS. I actually wrote a review of an earlier paper by the same group for my former lab's newsletter in December 2004. Leaving myself open to ridicule and correction, I have copied my original report word for word below without reading the new paper first. I wonder if the new study addresses any of the points I made in the final paragraph?

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Human endogenous retrovirus (HERV) transcripts are usually repressed by DNA methylation, but have been detected in patients with Multiple Sclerosis (MS) and other autoimmune diseases. The nature of this relationship remains unclear. Does re-expression of viral proteins trigger an autoimmune response? Can antibodies produced in response to another virus cross-react with HERV antigens? (Viral infections may be a trigger of MS). Or is expression of HERVs merely a result of reprogrammed DNA methylation, with no causal link to the disease? A recent Nature Neuroscience paper has finally provided some evidence for a causal relationship.

The paper focuses on syncytin, a HERV envelope protein. Syncytin was specifically up-regulated in the brain, demyelinating lesions and neuroinflammatory cells of MS patients. Expression of syncytin in cultured cells reproduced some aspects of the MS phenotype, including oligodendrocyte death and induction of proinflammatory molecules. Reproduction of these effects in cultured cells suggests that syncytin protein function, rather than an autoimmune response, may be involved in at least the initial neuroinflammatory aspects of MS.

The region of the mouse brain corresponding to that most affected in human MS was in infected with a syncytin expression vector. Infection reproduced some of the effects of human MS, including myelin damage, decreased numbers of oligodendrocytes, and induction of neuroinflammatory molecules. Infected mice performed poorly in behavioural tests, indicating muscle weakness and unsteady gait. Interestingly, treatment with antioxidants significantly reduced the molecular and behavioural effects of syncytin in infected mice and cultured cells. There is some anecdotal evidence that antioxidants can help control the symptoms of MS, but no large-scale clinical trials have been completed.

So there you have it – finally, some evidence to support the theory that HERVs are involved in MS. Personally, I'm most interested in the association that the authors didn't make. Syncytin is usually expressed mainly in the placenta, which may explain some aspects of MS epidemiology. Women are approximately twice as likely as men to develop MS, and the frequency of MS relapses can change during and after pregnancy. More work is needed to determine the mechanisms of syncytin activation in the placenta and in MS, and specifically the role of female hormones in this process. No doubt the paper by Antony et al will stimulate this, and other, avenues of investigation and debate.

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Canada has one of the highest rates of MS in the world. For more information, including how to make a donation, see the MS Society of Canada's website.