What evidence is there that ME/CFS is more autoimmune than chronic infection?

[Hip]

This seems like the same old infectious trigger theory that to my mind is obsolete.

What would be your take on the recent multiple sclerosis study, which found that MS is strongly associated with particular genomic variants of Epstein-Barr virus?

The evidence for an EBV association with MS is quite good anyway, but with this new study, the association seems to be placed on even firmer ground, as it would be hard to explain this link to EBV genetic variants if this virus was not playing a causal role in MS — a disease which I understand most experts consider autoimmune.

However, you are very good at finding flaws in theories, so it would be nice to have your views on this new study.


It would be interesting to examine the particular genes present in these EBV genetic variants linked to MS. What these viral genetic alleles are doing in the body might perhaps throw some light onto the triggering mechanisms of MS autoimmunity.

 

[Jonathan Edwards]

What would be your take on the recent multiple sclerosis study, which found that MS is strongly associated with particular genomic variants of Epstein-Barr virus?

The evidence for an EBV association with MS is quite good anyway, but with this new study, the association seems to be placed on even firmer ground, as it would be hard to explain this link to EBV genetic variants if this virus was not playing a causal role in MS — a disease which I understand most experts consider autoimmune.

However, you are very good at finding flaws in theories, so it would be nice to have your views on this new study.


It would be interesting to examine the particular genes present in these EBV genetic variants linked to MS. What these viral genetic alleles are doing in the body might perhaps throw some light onto the triggering mechanisms of MS autoimmunity.

An interesting paper.
Is the evidence for EBV being relevant to MS good anyway? I was not aware of that and the epidemiological evidence the authors quote is very indirect and soft.
The authors have clearly considered a non-causal association and looked for differences in MHC genotypes - which would explain differences in EBV protein alleles on the basis of different TCR repertoires. They did not find a difference in MHC but I think there may be other factors that could lead to a non-causal correlation.

As to whether MS is autoimmune - that I think is tricky. A lot of immunologists regard it as a T cell based autoimmune disease although I am not aware that we have evidence for T cell reactivity in humans - only in mouse models that are probably self-fulfilling. There is certainly immunoglobulin production in the wrong place (brain) and that I think is quite strong evidence for there being autoantibodies but nobody really knows what most of these antibodies are against. In a way MS does not really fit any neat category, but it does look like a dysregulation of B cell behaviour.

But I do think these data are quite suggestive of a role for EBV. The possibility that being colonised by certain EBV variants makes you more susceptible to MS is the simplest explanation for sure. I probably would not call this a trigger though. The patients are likely to have met EBV 10-30 years before getting MS. That suggests that EBV would be more of a threshold lowerer than a trigger. It is interesting that because almost everyone gets EBV we do not really know if EBV is a threshold lowerer for lots of autoimmune diseases - because there are no controls. But correlation with genetic variants would help solve that. EBV is of course different from all other microbes in this context in that it alters B cell function in all of us. And MS might be the choice candidate for a threshold lowering effect in that it may be not so much a disease of B cells attacking self as a disease of B cells wandering about too much because they are not kept tightly enough under control irrespective of their antibody specificity.

I certainly think that if this work is confirmed and becomes accepted as solid then looking at the same thing in ME would be worthwhile. A non-specific delinquency of B cells of a slightly different sort could explain why B cell depletion looks as if it might help even though no autoantibodies have been found

 

[Hip]

I certainly think that if this work is confirmed and becomes accepted as solid then looking at the same thing in ME would be worthwhile.

That would be interesting.


There were a couple of studies examining viral genomes in ME/CFS enterovirus infections:

Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome

Evidence for enteroviral persistence in humans

These studies found that ME/CFS patients with persistent enteroviral infections nearly always have viruses with a different genetic makeup compared to enteroviruses found in acute, self-limiting infections in healthy controls.

As far as I am aware, these studies, which were conducted around 20 years ago, have not yet been replicated, even though such viral genome studies seem to be a good way to assess whether a virus may be playing a causal role in a disease.

 

[halcyon]

I am not sure that there is good evidence for POTS having an autoimmune basis in general.

You don't think too highly of this study I take it then?

 

[Jonathan Edwards]

You don't think too highly of this study I take it then?

That study is interesting but it is the only one I know of. Knowing the technical problems involved in antibody assays I would want to see it confirmed by another group before taking it as firm evidence.

 

[halcyon]

That study is interesting but it is the only one I know of. Knowing the technical problems involved in antibody assays I would want to see it confirmed by another group before taking it as firm evidence.

I agree it's a tiny study, I hope it's repeated on a larger cohort. Do you think the hypothesis is sound though?

 

[Jonathan Edwards]

I agree it's a tiny study, I hope it's repeated on a larger cohort. Do you think the hypothesis is sound though?

The hypothesis is not unreasonable.

 

[Hip]

The Canadian Consensus Criteria specify three types of orthostatic intolerance that can occur in ME/CFS patients:

Neurally mediated hypotension (NMH)
Postural orthostatic tachycardia syndrome (POTS)
Orthostatic hypotension (OH)

As mentioned above, autoantibodies have been found in POTS in one study. And also, another study found autoantibodies in OH.

 

[BurnA]

I think those quotes relate to quite different questions. I do not have very strong feelings about the mechanism for POTS, if indeed PWME generally have POTS rather than some other form of OI. It is all a bit fuzzy to me. If OI occurs across the board in ME then I am tempted to think it is part of a secondary autonomic mechanism rather than being a sign of a specific aetiology, but I don't know. I am not sure that there is good evidence for POTS having an autoimmune basis in general.

This paper talk about increased POTS in CFS patients.
QJM. 2008 Dec;101(12):961-5. doi: 10.1093/qjmed/hcn123. Epub 2008 Sep 19.
Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome.
Hoad A1, Spickett G, Elliott J, Newton J.

But perhaps more interesting this paper identifies POTS symptom as a distint subgroup in response to exercise in CFS patients.

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome
A.R. Light,1,2,3 L. Bateman,1 D. Jo,1 R. W. Hughen,1 T.A. VanHaitsma,4 A.T. White,2,4 and K.C. Light1


Results
No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor’s transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup.



Do you know if POTS as a potential subgroup has been considered in your studies to date ?

Also, general query, i presume all samples for biobanks and general analysis etc are taken from patients at rest, is there any potential benefit to have samples post exercise ?

 

[voner]

This paper talk about increased POTS in CFS patients.
QJM. 2008 Dec;101(12):961-5. doi: 10.1093/qjmed/hcn123. Epub 2008 Sep 19.
Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome.
Hoad A1, Spickett G, Elliott J, Newton J.

But perhaps more interesting this paper identifies POTS symptom as a distint subgroup in response to exercise in CFS patients.

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome
A.R. Light,1,2,3 L. Bateman,1 D. Jo,1 R. W. Hughen,1 T.A. VanHaitsma,4 A.T. White,2,4 and K.C. Light1


Results
No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor’s transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup.



Do you know if POTS as a potential subgroup has been considered in your studies to date ?

Also, general query, i presume all samples for biobanks and general analysis etc are taken from patients at rest, is there any potential benefit to have samples post exercise ?

@Jonathan Edwards, I am bumping this, because I would also like to hear your replies to these questions posed by BurnA...

 

[Jonathan Edwards]

Do you know if POTS as a potential subgroup has been considered in your studies to date ?

Also, general query, i presume all samples for biobanks and general analysis etc are taken from patients at rest, is there any potential benefit to have samples post exercise ?

I am not actually doing studies myself. Dr Cambridge and colleagues are looking for subsets in terms of B cell biology.

Various groups have suggested post-exercise sample collection. It was discussed as being a useful further analysis at the IiME workshop.

 

[BurnA]

I am not actually doing studies myself. Dr Cambridge and colleagues are looking for subsets in terms of B cell biology.

Various groups have suggested post-exercise sample collection. It was discussed as being a useful further analysis at the IiME workshop.

OK but do they ever try to correlate subsets / findings in terms of symptoms or other features ? Or do you think symptoms are secondary and wont necessarily reveal too much in terms of B cell theory ?

 

[Jonathan Edwards]

Dear BurnA,
I really do not know any more than I have already mentioned - we all have to depend on what the research groups publish.

 

[RYO]

I do not know a lot about chronic post coxsackie myocarditis but I had thought that the virus probably only hung around for a relatively short period, with inflammation and cytokine production and that the chronic illness was due to subsequent cardiomyopathy due to structural damage. People tend to show some degree of stabilisation or recovery after the initial episode (if they survive), which would seem to argue against continued inflammatory change.

There is a small German study completed by Dr. Kuhl. He treated viral cardiomyopathy patients with evidence of persistent enteroviral RNA with high dose Betaseron with significant improvement.