Time to add another disease to the list of problems associated with wayward ERV expression:
Protective Effect of Human Endogenous Retrovirus K dUTPase Variants on Psoriasis Susceptibility
Repeat after me everyone:
ERVs are junk DNA. We WANT them to be junk DNA. Yes, very rarely an ERV is domesticated for Good, but almost universally, ERV expression is BAD.
While the main idea of this paper is neat, the experimental biology in this paper isnt very satisfying at all. There is no firm, obvious experimentally derived connection between ERV protein expression and disease, here.
For instance, the protein in question is a dUTPase, coded from a particular HERV K, in a particular region of your genome (chromosome 6). So, they looked for antibodies to that particular dUTPase in psoriasis patients, and healthy controls. Neat finding: On average, the psoriasis patients had more antibodies to this ERV dUTPase than the controls! Maybe antibodies to dUTPase are causing psoriasis!!!
Not so fast. They only looked for antibodies in 23 patients, and 16 controls. And, some psoriasis patients had the same levels of dUTPase antibodies as healthy people, and some healthy people had the same levels of dUTPase antibodies as the psoriasis patients. This is not a nice, obvious indicator.
So, they looked at cytotoxic T-cell responses to this ERV dUTPase in patients and controls. Neat finding: The psoriasis patients had CTL responses to dUTPase, while the healthy controls did not. Maybe its not antibodies, but cellular immune responses to an ERV protein that are causing psoriasis!!!
Not so fast. They only looked for CTL responses in 13 patients and 11 controls. And while 5 of the patients did have a CTL response to dUTPase, 8 didnt. Again, not a nice, obvious indicator or connection between wayward ERV expression and the disease.
The 'answer' to psoriasis isnt easy, and we shouldnt expect it to be, and thats not the authors fault.
What is nice about this paper is the genetics. Neat finding: After looking at the HERV K dUTPase gene in 708 patients and 349 controls, there were 14 single nucleotide polymorphisms (tiny changes) is psoriasis patients and not the controls. Five of those changes were statistically associated with psoriasis.
That is neat. Teeny tiny changes in an endogenous retrovirus are associated with psoriasis.
But the problem inherent in most research involving ERVs and diseases is still up in the air:
Why?
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What about psoriasis patients' antibodies and TCL response to other ERV proteins, relative to controls.
Here's why I ask that.
One possible explanation for the antibody and CTL findings would be that expression of this ERV protein is somehow related to pathogenesis of at least some cases of psoriasis.
An alternate explanation would be that psoriasis patients have disordered immune systems for reasons unrelated to the dUTPase but that the the results weakly measure the fact that they have disordered immune systems.
Likewise, psoriasis patients with ERV gene sequences more closely related to one another than the general population could mean that the ERV genes have something to do with psoriasis. Or that psoriasis has a genetic component, but that the ERV gene distribution in question is merely linked with whatever the real genes that actually matter are.
If psoriasis patients show association with reaction to/sequence of one or a few ERV genes/proteins, that would imply that the ERV genes are being expressed and doing something.
On the other hand, if psoriasis patients have indiscriminate exaggerated antibody/CTL response to vast numbers of ERV proteins, that might imply that the reactions are secondary to whatever is really going on in psoriasis, and that the genetic pattern reflects linkage of some ERV genes to whatever genes really matter, or psoriasis patients sharing recent common ancestry due to a local bottleneck..
Note that either would be an interesting finding.
OMGstix!!1 A typo! I just cain't buh-leeve et!!
Down about line 20; “(tiny changes) in psoriasis patients”
Really, dear, I know you're excited and everything, but .. really!
So fix it, and then benson this message please.
Wouldn't want any more anonymous denunciations re your standards worming their way to the bloglords, eh?
Hai!
Do you have an additional blog and/or a twitter account, Abbie? :)
Cheers
Here's another recent study that looked pretty neat, the beginning of the abstract talks about ERV's but the paper appears to be on antibodies to other RV's?-
Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia.
http://www.ncbi.nlm.nih.gov/pubmed/22542615
Question:
If scientists studying ERVs can perhaps find a link to something as complex as psoriasis?
Who thinks that maybe a stray ERV is responsible for ...
.... the mental disease known as "religion"?
I'm just sayin'...
... /end sarcasm
Eee, John, I wouldn't set too much store by that virus/psychosis paper. I'm personally of the opinion that measuring antibody responses is a bit of a bullshizzle way of looking at response to a disease. It's damn hard to do a really clean, definitive Western blot for a protein, even if you have great (often commercial monoclonal) antibodies that have no cross-reactivity (which, er, I have yet to find. I always get random ghost bands when I blot). Looking for evidence of viral RNA/DNA in blood or other tissues is nicer in my mind because it's much more specific, you can do a quantitative PCR, and *then* analyse your frequencies between cases and controls. They say themselves they use animal retrovirus antibodies to fish for reactions to human ERVs and RVs. It's a fishing mission which was always going to get some cross-reactivity! As the XMRV story tells, using cross-reactive antibodies leads to results you can't draw conclusions from.
If you look at their blots - so many are really, really messy. Lots of weird bands. Which is standard, but also a weakness of Western blotting.
Soo, a few reasons why they saw differences in antibody response (which they interpret as evidence for HERV activation)
- people with these disorders have immune disregulation as an integral part of this condition (correlative)
- HERV over-activity is *causing* their condition (causative)
- it's a statistical fluke, a false positive
- the meds they're on mess up their bodies & this somehow leads to HERV expression
- being a schizophrenic/psychotic puts you at risk of living in poorer housing, looking after yourself less, exposes you to nosocomial infections at a greater rate than the controls, leading to HERV expression somehow.
I would vote for a combination of the last three causing the results seen in this paper.