@Woolie, that's fascinating. I wonder given the absence of some key ME features like OI and brain fog and the spectacular response to prednisone if you don't have an unusual presentation of some autoimmune disease. I read somewhere that even in lupus it is possible to be ANA-negative.
Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?
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Hip
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Absolutely. With chronic hepatitis C virus infection of the liver, for example, only if you fully eradicate this virus with interferon does the disease disappear. If there is some virus left after the course of interferon, then the disease returns.
Hepatitis C patients are often give a year long course of interferon (which often causes considerable depression and misery as side effects), and for some this treatment eradicates the hepatitis C virus, and they are cured; for others, some of the virus remains in spite of the treatment, so they are not cured.
So this shows that it makes a big difference in such conditions whether you eradicate the virus or not.
I wonder if ME/CFS patients were give a full year long treatment with interferon, like hepatitis C patients get, would this then fully eradicate the enterovirus infection, thereby permanently curing their ME/CFS?
So how then, with your perspective, would you explain chronic hepatitis C virus (HCV) infection of the liver, that incidentally can produce symptoms very similar to those of ME/CFS?
Most people with the hepatitis C virus in their body are asymptomatic carriers: they have the virus, but do not display any symptoms. However, a small percentage of people with hepatitis C virus develop chronic hepatitis C.
Now, I have not looked in detail at all the research on HCV to see if there might be any immune abnormalities in those who develop hepatitis C disease.
However, in any case, the medical approach to treating chronic hepatitis C has been to develop antiviral and immunomodulatory treatments such as the year-long interferon treatment, and more recently, a new but very expensive drug called sofosbuvir (often used in combination with ledipasvir) which can fully eradicate the hepatitis C virus in nearly 100% of cases in just 12 weeks.
In other words, even if there might be an immune deficiency in those with hepatitis C disease, medical treatment is still focuses on developing antiviral and immunomodulatory therapies to eradicate the virus.
If the pharmaceutical industry applied similar dedication to developing a drug that could eradicate coxsackievirus B and echovirus infections, we may well have a drug that can cure ME/CFS in 12 weeks as well.
halcyon
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If nothing else, you'd think that they'd work on one in response to enterovirus 71 or D68. China at least has a number of vaccines in the works for E71, but we're never going to have a vaccine for all the enteroviruses so I think a drug is still needed. A drug could also potentially be useful for post-polio patients as well as viral myocarditis patients. It could potentially end a lot of suffering.
Hip
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Going back to the chopped up RNase L that hampers clearance of intracellular enterovirus infections:
A while ago I was looking at theoretical ways of preventing RNase L from being chopped up (cleaved). Although several factors are known to cleave RNase L, including elastase, Rich Van Konynenburg thought that m-calpain released in the cell was the most likely culprit responsible for the chopping up.
So my thoughts were, if we can inhibit calpain release in the cell, this may prevent RNase L getting chopped, so that RNase L can then do its job of clearing the intracellular enterovirus infections.
A while ago I was looking at theoretical ways of preventing RNase L from being chopped up (cleaved). Although several factors are known to cleave RNase L, including elastase, Rich Van Konynenburg thought that m-calpain released in the cell was the most likely culprit responsible for the chopping up.
So my thoughts were, if we can inhibit calpain release in the cell, this may prevent RNase L getting chopped, so that RNase L can then do its job of clearing the intracellular enterovirus infections.
Jonathan Edwards
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The list has been going on and on since the 1960s but there is virtually no evidence. I looked at a few of those titles and they are just reiterating fairytales or including diseases that are not autoimmune. Proven precipitation of autoimmunity in humans by infection is a very unusual situation. What particular examples did you have in mind? (E.g. Coxsackie myocarditis and rheumatic fever are not autoimmune - there is no good evidence of adaptive immunity to self.)
Jonathan Edwards
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Autoantibodies can produce disease through lots of mechanisms that do not involve inflammation - like pernicious anaemia, myasthenia, immune thrombocytopenia, where inflammation markers are likely to show nothing. Antibodies to endothelium might generate inflammation but might not. They might just cause internalisation of the antigen on the endothelial cell. If you have a consistently high CRP and low albumin you probably do have an inflammatory process - maybe something quite different from most PWME. ANA is only present in a small minority of autoimmune diseases.
What about EBV and multiple sclerosis? From my understanding the MS research community has come to the definite conclusion that EBV is required to trigger MS, if you don't have EBV in your body it's impossible to get MS.
Yes I understand that almost all adults have EBV and only a small percentage actually get MS in their lifetime so there must be other factors, but EBV infection is a required factor.
And if I'm not mistaken more and more evidence is showing that EBV is more intricately involved in the demyelinating autoimmune process than previously thought.
For example:
Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy
http://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses
Epstein-Barr virus-specific adoptive immunotherapy: a new horizon for multiple sclerosis treatment?
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Allen Steere, inadvertent discoverer of Lyme, maintains that continued arthritis in the knees of Lyme patients following treatment is Borrelia infection-induced autoimmunity.
Bad example, leokitten and Jonathan, for various reasons, but just because I don't care for the man doesn't mean his theory isn't correct. So, it may be relevant.
Bad example, leokitten and Jonathan, for various reasons, but just because I don't care for the man doesn't mean his theory isn't correct. So, it may be relevant.
Hip
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This cleaved, low molecular weight RNase L found in ME/CFS is usually described in the literature as "dysfunctional", so my assumption has always been that this RNase L does not do its normal job of clearing out intracellular viral RNA from the cell.
However, I have just now tried to find some definitive statements about this reduced antiviral activity of the low molecular weight RNase L that I am assuming, but cannot find any. So perhaps there is actually no info available as to whether it has a reduced antiviral action or not. I may have been assuming it, but right now I can't seem to find any evidence for it.
Certainly the low molecular weight RNase L does a lot more damage in the cell that normal RNase L, that we can say.
Jonathan Edwards
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People have been saying EBV is a necessary cofactor for disease X since the 1980s at least. It is very plausible that B cell mediated diseases require the transforming effects of EBV to get started but as far as I know this is pretty untestable and remains unproven across the board. Even in Burkitt lymphoma, which gave EBV the name 'Cancer Virus' does not seem to be dependent on the transforming effect despite the fact that it would seem obvious that it would. So I agree that it is possible that EBV is a necessary cofactor for MS but that is rather different from what people tend to mean by trigger. EBV infection is mostly in infancy. MS occurs mostly around 20-40.
I have never heard of the idea of EBV being involved in demyelination before. The MS community are divided in opinions on virtually everything and although you are bound to find a review article pushing one theory or another I think this is largely a reflection of the proliferation of review journals that make money out of science by distributing drivel.
The other point is that we do not know that MS is autoimmune. It may well be, but so far what we know is that antibodies are made in the wrong tissue (brain), not that these antibodies are necessarily directed against self. There are lots papers suggesting that they are directed against myelin proteins but when I last looked at the field I was not convinced that this was a hard finding.
My feeling is that both in MS and ME we may need to change gear on our ideas about antibodies. Here is an example hypothesis. For antibodies to be 'anti-X' in a functional way in plasma they really need to have a dissociation constant of something like ten to the power minus 8. However, if they are picked up by immunoglobulin Fc receptor 1 (CD64) then because of the thermodynamic stabilisation of receptor binding they may function as 'anti-X' with a dissociation constant of - say - 10 to the -6. In most tissues this does not matter much because a macrophage with CD64 receptors will pick up a random assortment of antibodies and so only a tiny fraction will function as anti-X and nothing will notice. However, if a microglial cell with CD64 in the brain is bathed in oligoconal antibody that is anti-X at a 10 to the -6 level it may gobble up X. Since low affinity often goes with broad specificity there is a reasonable chance that some myelin protein will stick at 10 to the -6 so you have lift off. But if you do standard ELISA assays for autoantibodies with vigorous washing that only leave 10 to the -8 binding on the pate you will never know. (The actual numbers are made up here, you will realise.)
So maybe in ME we have some antibodies to endothelial cell receptors or neurotransmitter receptors which you will never find in an ELISA. They will only function if bound to CD64. And the result of CD64 binding may be interferon production. Gamma interferon switches CD64 on, so you might have the possibility of continued grumbling interferon production very locally with no other signs of inflammation. I doubt all of that will hang together but it is the sort of idea I think we may need to consider.
Jonathan Edwards
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I suspect he is thinking along the lines of reactive arthritis - where you get persistent arthritis following intracellular infections of various sorts. That has never been shown to involve autoimmunity but many people do not make the distinction. So you are probably right that it is a bad example - but relevant in that it is the common confusion that makes people write reviews on infection and autoimmunity.
Jonathan Edwards
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I have never come across reference to this RNase L at scientific meetings - only on PR. Do we actually have any reproducible data about it in ME, or is it another unconfirmed report from a private lab?
lansbergen
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KDM and WPI
Woolie
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Maybe. On ICC criteria, I count as "atypical" CFS. If it is lupus, I'm pretty lucky to be still alive and no detectable damage 25 years after onset, and with no medication till a couple of months ago. On the other hand, how many of us have something unusual in our presentation? Something that's not typical? Seems this is a family of illnesses. Or all the same underlying etiolgy but with different manifestations?
(sorry, edit that: 25 years).
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Well, Jonathan, I suppose it's true only the shepherd distinguishes the sheep. I certainly don't know the difference between reactive arthritis and autoimmune arthritis.
But I can tell you Steere is writing a lot about activated T and B cell responses to an autoantigen in synovial tissue. Specifically, he speaks to endothelial cell growth factor, ECGF, and associated responses in both T and B cells.
He thinks his theory is further bolstered by the presence of genetic HLA-DR alleles that are said to be common in Lyme patients with refractory Lyme arthritis.
I cannot say whether this characterizes an autoimmune response or reactive arthritis. I'm pretty sure Steere does not think any Bb antigens are at play here, which would seem to indicate something other than reactive arthritis.
Now, I must confess that if you are correct, and Steere is misusing the qualifier "autoimmune", I will be neither surprised nor disappointed.
But I can tell you Steere is writing a lot about activated T and B cell responses to an autoantigen in synovial tissue. Specifically, he speaks to endothelial cell growth factor, ECGF, and associated responses in both T and B cells.
He thinks his theory is further bolstered by the presence of genetic HLA-DR alleles that are said to be common in Lyme patients with refractory Lyme arthritis.
I cannot say whether this characterizes an autoimmune response or reactive arthritis. I'm pretty sure Steere does not think any Bb antigens are at play here, which would seem to indicate something other than reactive arthritis.
Now, I must confess that if you are correct, and Steere is misusing the qualifier "autoimmune", I will be neither surprised nor disappointed.
I agree that it is possible for a subset of PWME there is a chronic infection component, but as I said I don't think it is so much the root cause that many others think anymore.
There is also one major problem in your analogy, enteroviruses are so easy to catch over and over again. Unlike hepatitis C which can only be passed through sexual contact or sharing needles etc, if you had to do year long interferon treatment or 12 weeks/$85,000 harvoni or other next gen treatment you would likely catch enterovirus again soon after being cured. And do you do this over and over again? It's not feasible.
I think the brute force approach of eradicating virus just isn't a feasible approach for all viruses. We need to look at different treatment approaches and understanding what subtle flaws there are in people's immune systems which are causing them to have symptomatic chronic infection.
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Jonathan Edwards
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People do write a lot about autoantigens in synovial tissue - but nobody ever found a response to one and if you look at the anatomy it would make no sense anyway. But then most people don't bother with the bigger picture. HLA-DR alleles are likely to be associated with response patterns to microbes - when I did my doctorate they were called 'Ia' or immune response associated genes. No need to extrapolate to autoimmunity.
In reactive arthritis the antigens from the organism have long disappeared. There is a persistent hyperactivity of T cells that seems to involve IL-17. The T cells at fault are addressin-domain specific (skin, gut, mucosa, other) but nobody has shown that they are self-reactive. You might ask why T cells should produce inflammation in the absence of organisms if they are not self-reactive and I think the answer is that T cells can be activated through innate pathways and if thresholds are lowered enough, for reasons we do not understand, except that the B27 allele is relevant, then T cells may play havoc without needing any stimulus from specific antigen. Remember that T cells will invade a knee twisted in a football game. They may need a constant wafting of LPS from general bacterial debris to remain activated in reactive arthritis but even that we have no good evidence for.