The connection between wayward endogenous retroviral protein production and multiple sclerosis is tightening :D Sure its still a mess, sure we dont have all the pieces to The Puzzle-- but weve got a strong foothold now. We know we are going in the right direction.
A subtle paper just came out in 'Journal of Virological Methods'. They dont have some earth shattering revelation or sexy data to report... they have a reagent.
There are lots of ERVs in your genome. They get divided up into families, depending on how much they look like whats alive today, and what tRNA they (used to) use to start reverse transcription. HERV-Ks use lysine, HERV-Hs use histidine, etc. The HERV-W family already has a claim-to-fame-- Syncytin.
We got all excited when we found a connection between syncytin and Multiple sclerosis. Either expression of this placental gene in brains is a cause of MS, an effect that perpetuates the cause, or just an 'innocent' effect, making this protein a marker for disease that might help with pre-symptomatic diagnosis. YAY syncytin!
... Except the ERV protein that is being expressed in MS patients isnt syncytin.
We thought it was syncytin because we have antibodies that detect syncytin, and they worked, and we used PCR primers for HERV-W and they worked...
But its actually a different HERV-W! Mameli et al did something very simple, conceptually, but very important-- they created PCR reagents that could differentiate between syncytin and a different putative HERV-W, 'MS associated retrovirus', MSRV.
Know how I always tell Creationists we can tell ERVs apart? MSRV has a teeny-tiny deletion in a portion of envelope. Mamelis group capitalized on that teeeeeny difference to ask if its this MSRV and/or syncytin making noise in MS patients. One set of reagents that could 'see' syncytin, but not MSRV. Another that could 'see' MSRV, but not syncytin.
So they used their reagents on blood samples from patients diagnosed with MS from a local hospital and healthy volunteers, and brain samples from MS/'healthy' people who had donated their bodies to science.
Syncytin levels were even across the board.
Its MSRV that is elevated in MS patients. A different ERV.
Not only that, but MS patients undergoing therapy had lower levels of MSRV than untreated patients.
AAAAND, there were a couple of healthy controls with MSRV present!
So this paper isnt going to be in Nature or Science for determining what causes MS. But they did make an awesome reagent that will help future scientists figure it out! The experiments wont be easy, but we can do it!
For instance-- Enroll a cohort of kids. Families with/without history of MS. Do these kids express MSRV? Maybe no one does... until they are infected with Epstein-Barr Virus, or one of the other herpes viruses that have been suspected of 'turning on' wayward ERVs? Or maybe lots of the kids do express MSRV, but it takes a long time for it to start causing problems-- you have MRSV early, but the disease doesnt come until later? Can we treat people who test positive for MRSV early and prevent MS?
Can we treat MS patients with anti-MSRV antibodies? What about people who just test MSRV positive-- do anti-MSRV antibodies prevent the suspected inflammation they cause, and prevent the subsequent MS-autoimmunity?
Oh yeah, which reminds me to say-- you dont make antibodies to MSRV. Its part of your genome. And it looks like syncytin. Its self. You wont 'attack' MSRV any more than you would 'attack' your own red blood cells. So any anti-MSRV antibodies we treat with will have to be generated by a pharm company, cause you aint gonna make them on your own.
So, the water is still very, very muddy. But we know we are on the right track!
I've been following MS and ERV story a little--is this also induced by EBV and HHV-6A? There are a few paper that suggest the transcribed HERV's are implicated in the auto-immune problems that lead to demyelination.
It also looks like some of the research is suggesting that a variety of stresses(2) (viral infection, possibly other "stress") can induce transcription of HERV components (1) which may explain some of what MS patients say: "I was find until I had the flu" or "stress caused my MS to get worse"---
1.HHV-6A infection induces expression of HERV-K18-encoded superantigen.J Clinc Virol 2009 Sep;46(1):47-8. Epub 2009 Jun 7.
2. Endogenous retroviruses in systemic response to stress signals. Shock 2008 Aug;30(2):105-16.
"Oh yeah, which reminds me to say-- you dont make antibodies to MSRV. Its part of your genome. And it looks like syncytin. Its self. You wont 'attack' MSRV any more than you would 'attack' your own red blood cells."
Ahhh silly adaptive-immunologists.
Ok, so you don't attack your own RBCs. But your macrophages can respond to the hemozoin that gets formed in them during malaria infection.
In addition, there was a great TLR2 paper out there from a few weeks ago showing that TLR2 could recognize both a weird complex from gut microflora and an aggregated protein connected to Alzheimer's (these proteins have nothing to do with each other genetically, but seem to share certain structural characteristics). And just recently, there was a paper linking the TLR2 PARP1 pathway to... wait for it...MS!
Anychance MSRV is a TLR2 ligand?
Forgive me if I'm mixing things up, but I have a feeling I heard something about MS recently - that it actually comes in a spectrum of expressions. Some people are unsymptomatic and only diagnosed post mortem. I wish I could remember where I heard it to make sure I'm not confusing it with another condition.
Anyway, if this is actually the case, then doesn't it make sense to find the 'marker' in unsymptomatic people? Or is there some more conventional markers that can unambiguously detect MS in non-symptomatic 'sufferers'?
How embarrassing - I still don't know the one-letter codes for the AAs (of course, I don't know the AAs either, so ...)
@Sili - " Some people are unsymptomatic and only diagnosed post mortem. "
Yes, this is true. Some people do go to their grave without ever having known that they had MS.
The spread of the level of disability among patients is VERY wide.
As a developer of legacy systems - and therefore, a hacker - I must tip my hat to your profession: Untangling the web of spaghetti code and chained dependencies is difficult enough; I'd hate to have your job - to have the intermediate step of protein sequencing, the inability to directly unit test, and the difficulty of implementing and observing changes to a live system in a reasonably consistent manner.
You have my respect: your sort hacks at the hardest machines that exist.
@Sili: "I wish I could remember where I heard it"
Was on a recent episode of the Skeptic's Guide?
They were discussing this story:
O/T Has something happened to Wee Willie Winkie? I don't recall seeing him post recently.
Thank you so much for posting this. It makes those of us whose family members have MS feel like our efforts to raise money and awareness are paying off. You really made my day.
Keep up the awesome.
Bingo! Thanks, Fitz.
I kept thinking that it had to be the Guardian Science Weekly - I don't know why the SGU didn't register at all.
Glad to hear I hadn't mixed MS up with something else. (At least not in this case.)
Interesting read. Thanks for posting.