Epstein-Barr virus protein can “switch on” risk genes for autoimmune diseases

Gingergrrl said:
I am not looking for jolly discussions, I just wish we were allowed to discuss it at all without being told it is BS within the first few posts which tends to shut down discussions for those of us who do not think it is BS.
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Hi @Gingergrrl, I don't see it a shutting down debate. When a scientific idea is being discussed, I am glad that there are a few experts on the forum who can give their perspective based on their knowledge on the subject. And I'm grateful for their patience in answering questions and explaining when we have misunderstood something.

I hope other scientists with expertise in all areas of medical research join the forum to share their knowledge with us too.

I gather at scientific meetings where experts in a particular field talk about their research there is plenty of debate about the validity of each others' findings - I certainly hope so. That's part of how science advances.

I think it is hard for people like you and me who don't have the depth of knowledge to discuss things like this - in the end all we can do is listen, try to understand, and decide which expert we believe.
 
Gingergrrl said:
I am not looking for jolly discussions, I just wish we were allowed to discuss it at all without being told it is BS within the first few posts which tends to shut down discussions for those of us who do not think it is BS.
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Of course you are allowed to discuss stuff, @Gingergrrl. But if some of us think it is hype and nothing new surely we are allowed to say that too? What would be the point in waiting for twenty posts before suddenly saying it? The thing about science is that it isn't about whether something sounds nice, it is about whether it makes sense or is new or well evidenced.
 
Can someone please explain this bit from the patent?

"Applicant assembled 53 European ancestry SLE loci (P<5.times.10.sup.-8) with risk allele frequencies >1%, constituting 1,359 plausibly causal SLE variants. To explore the possible environmental contribution from EBV, Applicant evaluated the ChIP-seq data from EBV-infected B cells for the EBV gene products EBNA1, EBNA2 (three datasets), EBNA3C, EBNA-LP, and Zta (Supplementary Data 2). EBNA2 occupies loci that significantly intersect SLE risk loci in all three available ChIP-seq datasets (Table 1). For example, 26 of 53 European SLE GWAS loci contain DNA immunoprecipitated by EBNA2 in the Mutu B cell line, an almost 6-fold enrichment (Pc<10.sup.-24). No association was detected for the other EBV-encoded proteins. To examine the possibility that these results might simply be explained by enrichment of SLE loci in B cell open chromatin regions, Applicant restricted the RELI null model to variants located in DNase hypersensitive regions in EBV-infected B cells. With this higher stringency null model, all of the EBNA2 associations remained significant. Thus, the associations Applicant detect between SLE risk loci and EBNA2 cannot simply be explained by the previously established strong co-localization between SLE risk loci and B cell regulatory regions in the genome.sup.23."
 
Jonathan Edwards said:
But if some of us think it is hype and nothing new surely we are allowed to say that too?
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Sorry, I didn't mean that you (or anyone!) wasn't allowed to say it. I just wish there could be more of a discussion amongst the individuals who are experiencing the illness or have certain symptoms or got certain tests results. I find it strange that both of my doctors (who are really solid with 30+ years of experience each) both believe without hesitation that EBV can cause autoimmunity and that it did in my case. I find it exciting that this concept (whether brand new or centuries old) is currently being looked at. I guess I don't mind a four minute video by the researchers and didn't view it as hype at all (which is maybe just a communication or stylistic difference, I don't know)!
 
Hutan said:
Can someone please explain this bit from the patent?
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I have not looked through this in great detail but this is what I think they are saying. They find that the EBV protein EBNA binds like a transcription factor to certain human genes. Transcription factors are small proteins that turn gene usage on and off. So it is likely that EBNA turns these human genes on or off as part of EBVs cunning strategy to fool B cells.

They find that several of the genes EBNA binds to are genes involved in B cell regulation. Not surprising if EBV lives by fooling B cells. But they specifically find that EBNA binds to genes that have polymorphic/variable alleles that confer risk for SLE. I do not know which they are talking about but for instance the complement C1q and C4 genes have variants that give risk for SLE. So maybe EBNA binds to these.

That would still not be very surprising because we would expect genes that specifically control selective growth of B cells would give risk for SLE - and they do. And again we would expect EBV to go for those because we see loss of selectivity in B cell growth during mono.

But there seems to be a huge illogical jump somewhere next. If genes A,B,C and D confer risk for the regulatory error that is lupus, which seems to be some sort of aberrant feedback loop, and EBNA binds to those genes that in no way implies that EBNA is likely to cause lupus. Lupus is not caused by these genes being switched on or off. It is caused by having defective copies of the genes that mean that the regulatory set of the immune system is skewed all the time.

The key point is that the epidemiology is wrong. If EBV caused lupus we would expect lupus to show up shortly after EBV infection and it does not. We would also expect there to be more lupus in people who have had EBV than those who have not. Very few people do not get EBV but there are documented cases of lupus in some of those. There are probably no reliable figures but I am pretty sure there is no evidence for lupus being more common in people who have had EBV.

My mother and Patrick Venables looked at all this in 1985. Patrick spent about twenty years trying to show that EBNA was involved in rheumatoid arthritis or lupus but nothing ever came of it. The idea that EBV might drive these autoimmune diseases was obvious to everyone as soon as the virus was discovered because it was known to expand B cells. But despite several people devoting their careers to it nothing fitted together.

The findings talked about by the Cincinatti people are very interesting if you are interested in how EBV expands B cells but that is all as far as I can see.
 
Apologies if this is a dumb question... but I’m not sure I am totally clear about what you are saying @Jonathan Edwards ...
If B cells are switched on by diseases, does that mean that the more diseases you have had/the more your B cells have been switched on, the more likely you are to develop auto-immune disease? Is the development of a reaction to self just bad luck?

In my head, I have understood this to be why people who get one auto-immune disease are more likely to develop another.
 
Daisybell said:
Apologies if this is a dumb question... but I’m not sure I am totally clear about what you are saying @Jonathan Edwards ...
If B cells are switched on by diseases, does that mean that the more diseases you have had/the more your B cells have been switched on, the more likely you are to develop auto-immune disease? Is the development of a reaction to self just bad luck?

In my head, I have understood this to be why people who get one auto-immune disease are more likely to develop another.
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No, as far as we know switching B cells on is perfectly normal and the immune system is designed to do it all the time and switch them off when they have done their job. Autoimmunity is all about a loop where you switch on B cells that react to self and cannot turn them off. As far as we know from the epidemiology forming this sort of loop has nothing to do with how often you stimulate your B cells in response to microbes.

Developing more than one autoimmune disease is probably a genetic risk thing. If your immune system is programmed to tend to trip into loops it may do it more than once.

Another point is that for each autoimmune disease only one very specific set of B cells (out of tens of thousands or millions) is switched on. What the others are doing is irrelevant.
 
I found this very interesting and exciting too.

Citation: Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, et al. (2017) Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray.
PLoS ONE 12(6): e0179124. https://doi.org/10.1371/journal.pone.0179124

With the use of NG whole genome sequencing and whole -omics studies, I feel that there is a surge in interest in the herpes virus family especially now that the "wet lab" data seems to have suffered a crisis in reproducibility/repeatability.

I am no expert though and so recognise that the hype can influence me far too much.

My background is an old degree in Genetics, BMS in Haem and Immunology and I worked with human brain tissue (Stanley Foundation Neuropathology Consortium) doing a pilot study using RT qPCR looking at viral loads of the beta herpes virus in 3 small groups (n=15) normals, schizophrenics and major depressive disease. We found evidence of only HHV6A in the brain tissue but I crashed during the work, the department was folded and so no publication. (The beta herpes group is CMV, then 6A and 6B and 7 so not EBV).

However during my literature research there is plenty of evidence for EBV being a master at controlling both host immune system and some other HHV in host.

I am hopeful that these new technologies will enable previously unseen pathological pathways to be illuminated. However I feel they might take some time to emerge clearly from their new field of -omics.
 
To be honest I have limited knowledge and it's probably more accurate to say "some knowledge" and am aware this can give me a wholly biased nonsense view. Hence I see it as such and very clearly just my humble opinion in my own tin-pot way.

However I do wonder now that technology is advancing and becoming so personalised and precise, then maybe new paradigms might appear about how everybody views the impacts of lifelong latent viruses like the HHVs.

So yes I feel that the sub-groups in ME/CFS will be emerging.

I know the Japanese seem to be ahead of the curve or maybe that is because they have a different strain of EBV over there.?

Who knows but hopefully "they" will begin to look. In fact I feel they have already started and we'll get to see via published papers in time.
 
Gingergrrl said:
Sorry, I did not realize you meant EBNA (and that is one of the tests I have been positive on since having Mono). I just Googled yonks (and still don't know what billy means!) and I sometimes feel I do not know enough British terminology to follow some of these discussions (but that is my fault, and not a criticism)!



For me it was a short four minute video that was explaining to colleagues and lay-people what they found and what they hope to research further. For me it doesn't matter if they are excited about their findings (vs. sobered and measured which is your preference). I just want to hear the findings and if more doctors & researchers understand that there is a connection between EBV and autoimmunity, this is thrilling to me and backs up what both of my doctors believe occurred in my case. And this is a major hospital, not some random sketchy clinic.



I am not looking for jolly discussions, I just wish we were allowed to discuss it at all without being told it is BS within the first few posts which tends to shut down discussions for those of us who do not think it is BS.



I do not consider research on EBV and autoimmunity to be pseudoscience (and have no idea what a 50% payday loan is). Maybe I am just more suited for the other board as much as I really do like this one, too.
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'Like billy-oh' - in this context means 'like mad' or 'a lot'. It typically means 'an extreme example of something'. Also Billy-o, Billy-ho, etc. Not to be confused with Billy No-Mates (meaning 'on your own' or 'a loner'), although I suppose the two could be connected (with Billy No-Mates being the extreme example of a person without friends). See here: https://www.phrases.org.uk/meanings/like-billy-o.html

'Payday loans' are short-term loans supposed to cover you until payday. So typically only a month or so. They're usually much higher interest than standard loans, and only for small sums of money. It's basically a kind of legalised loan shark here in the UK, because such loans are targeted at the poorest and least able to pay such exorbitant rates (but they're easy to get approved for).

'Yonks' means years, or at least ages. As in: 'I've not seen John Smith for yonks! He always was a right Billy No-Mates! He was so daft he wouldn't even get approved for a payday loan...' etc etc. Except now I have to explain 'daft' (silly, stupid, ignorant).
 
Andy said:
Haven't been following the rest of the discussion in this thread but Chris Ponting posted this earlier on Twitter.
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I am puzzled - not sure what Ponting is meaning.

We know the genes that when faulty confer risk for lupus and we can see why they might. We have a.lso had reasonable ideas of mechanism for nearly twenty years.

This paper shows that EBNA binds to these genes but that does 'identify a mechanism' because EBNA does not cause lupus, as far as we know. We knew the mechanisms and EBNA turns out to use the same mechanisms to replicate EBV but I don't think it tells us anything terribly interesting about EBV clinically since in the end the B Cells are controlled by CD8 T cells and people get better.
 
There is a new blog on this.
The study – produced by researchers at Cinncinnati’s Children Hospital – demonstrated that once EBV infects B-cells, it turns on genes that have been identified as risk factors for a boatload of autoimmune diseases.

It turns out that even though the virus is, so to speak, latent; i.e. it’s not replicating – its transcription factor is still active – altering the expression of our genes. The genes that it affects just happen to be the same genes that increase the risk of developing lupus, multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes. Apparently decades of genetic assault from EBV’s transcription factor can set the stage or at least contribute to many autoimmune diseases.

Chronic diseases are usually caused by a variety of genetic and environmental factors. Because not everyone with these transcription factors comes down with a chronic illness, other factors must play a role. The authors believe, though, that the gene expression changes induced by the virus in the B cells could account for a large number of people with lupus and MS who fall ill.

“In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases,” Harley
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Opportunities for Collaboration Open Up
The big question awaiting ME/CFS now is if the abnormal transcription factors associated with the autoimmune diseases in the recent paper are present. The good news is that a study determining that appears to be within reach of an ME/CFS researcher with the technical ability and funds. In an unusual move, the Cincinnati researchers are making the computer code they used available to other researchers.

“We are going to great lengths to not only make the computer code available, but all of the data and all of the results. We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow-up on them.” Weinrauch
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http://simmaronresearch.com/2018/04/autoimmune-virus-groundbreaking-ebv-finding-help-explain-mecfs/
 
I came across the article - in fact, there's a second article about that paper:
https://www.nih.gov/news-events/nih-research-matters/epstein-barr-virus-autoimmune-diseases
Interesting.

Jonathan Edwards said:
It is a pity that scientists hype their work so much these days.
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Where's the hype?
The paper is published in Nature. Has Nature become crap, too (or is a bit like Cochrane)? Or only when it comes to medicine? If so, should one assume any journal is potentially low-qualitative if it comes to medicine?

I just know from Physics, Chemistry and Biochemistry that, indeed, only some of the best works end up in Nature or Science. Some colleagues phantasized about a paper in Nature. :) It would have ensured their careers.

Edit: Ok, I see some interpreted the stuff as hype. Understood.
 
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Indigophoton said:
Hype may not be apparent to those insufficiently familiar with a particular field, but for anyone who works in or near that field, who is any good, it is, actually, an immediate first indicator of a less good scientist/paper.
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Hm, I don't know if that's a general rule.

There was a physics group at the Uni where I did my PhD (our group made simulations for them) which discovered (new) nanomaterials. Their results were widely hyped. The problem is: Their findings were really good; I didn't like them (pretty arrogant), but their science was excellent.
 
Inara said:
Where's the hype?
The paper is published in Nature. Has Nature become crap, too (or is a bit like Cochrane)? Or only when it comes to medicine? If so, should one assume any journal is potentially low-qualitative if it comes to medicine?

I just know from Physics, Chemistry and Biochemistry that, indeed, only some of the best works end up in Nature or Science. Some colleagues phantasized about a paper in Nature. :) It would have ensured their careers.
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Yes Nature has become crap - certainly in medicine.
 
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