Do MEs cause CFS?

[Snow Leopard]

My experience is different. I do get crashes from cognitive activity, but those crashes are primarily cognitive in nature. I don't get full body aches from it, or swollen lymph nodes, whereas I do get those symptoms from physically-triggered crashes.

Same.

Mental exertion does not trigger PEM in the rest of my body - yet exertion of the rest of my body causes cognitive symptoms from PEM...

 

[MeSci]

What is clear is that you can get severe fatigue in both B and T cell related diseases even if the specific immune or clinical signature of the disease is pretty hard to detect or short lived.

If it is short-lived, would/could that mean that the specific immune or clinical signature of the disease might not be detectable at all after symptoms commence? And what exactly do you mean by the signature?

 

[Jonathan Edwards]

If it is short-lived, would/could that mean that the specific immune or clinical signature of the disease might not be detectable at all after symptoms commence? And what exactly do you mean by the signature?

In reactive arthritis the joint problems and associated signs like nail lifting may only last a few weeks but the fatigue may continue long term. In B cell related diseases the autoantibodies tend to continue so they are less of a problem. However, if there is just a modest antinuclear antibody level then if initial clinical signs, like rash, fade rapidly then doctors may be doubtful about making a clear autoimmune diagnosis.

 

[Hutan]

What I think may be an important difference is that we have very little evidence for B cell autoimmunity being triggered by infection or environmental stimulus.

@Jonathan Edwards, did you see the following report discussed on another thread 'Myasthenia gravis rituximab trial'? (http://forums.phoenixrising.me/inde...avis-rituximab-trial-in-us.38527/#post-615000)

I know you don't like the molecular mimicry idea, but I think even if that speculation is ignored the point of this article (which was that a link was being found between west nile virus and myasthenia gravis) is still interesting.

Muscle Nerve. 2014 Jan;49(1):26-9. doi: 10.1002/mus.23869. Epub 2013 Sep 11.
West nile virus infection and myasthenia gravis.
Leis AA1, Szatmary G, Ross MA, Stokic DS.
Author information

Abstract
INTRODUCTION:
Viruses are commonly cited as triggers for autoimmune disease. It is unclear if West Nile virus (WNV) initiates autoimmunity.

METHODS:
We describe 6 cases of myasthenia gravis (MG) that developed several months after WNV infection. All patients had serologically confirmed WNV neuroinvasive disease. None had evidence of MG before WNV.

RESULTS:
All patients had stable neurological deficits when they developed new symptoms of MG 3 to 7 months after WNV infection. However, residual deficits from WNV confounded or delayed MG diagnosis. All patients had elevated acetylcholine receptor (AChR) antibodies, and 1 had thymoma. Treatment varied, but 4 patients required acetylcholinesterase inhibitors, multiple immunosuppressive drugs, and intravenous immune globulin or plasmapheresis for recurrent MG crises.

CONCLUSIONS:
The pathogenic mechanism of MG following WNV remains uncertain. We hypothesize that WNV-triggered autoimmunity breaks immunological self-tolerance to initiate MG, possibly through molecular mimicry between virus antigens and AChR subunits or other autoimmune mechanisms.

Dr. Leis noted that he is seeing more cases of WNV and predicts an increasing number as time goes on. So far, he has .... just received 3 more case referrals of MG from colleagues, for a total of 9. He has published this work in an article online in Muscle & Nerve, and it will later appear in print.

 

[Jonathan Edwards]

@Jonathan Edwards, did you see the following report discussed on another thread 'Myasthenia gravis rituximab trial'? (http://forums.phoenixrising.me/inde...avis-rituximab-trial-in-us.38527/#post-615000)

I know you don't like the molecular mimicry idea, but I think even if that speculation is ignored the point of this article (which was that a link was being found between west nile virus and myasthenia gravis) is still interesting.

It is interesting as a clinical observation but one would need to know the probability of this turning up by chance. One of the problems, as they allude to in the paper, is that people with other neurological diagnoses rather often turn out to get diagnosed with MG probably because the MG was there at a subclinical level beforehand and significantly contributed to the person getting to see a neurologist. MG is not that rare and a lot of it goes undiagnosed.

 

[greeneagledown]

What I think may be an important difference is that we have very little evidence for B cell autoimmunity being triggered by infection or environmental stimulus. And that makes sense because B cells employ a chain reaction in their activation which can start up without external input.

@Jonathan Edwards, here is my understanding of your position: There may be a subset of ME patients whose underlying pathology is some sort of auto-immune disease, and if so, this auto-immunity almost certainly wasn't triggered by an infection. Is that a fair characterization?

I find this hard to square with what we saw in the phase 2 open-label Rituximab trial. 7 of the 28 patients went into long-term remission after just 5-6 infusions. Because their remission was long-term, it seems like they must have an auto-immune disease and Rituximab broke the feedback loop. (I believe you have previously said that long-term remission from Rituximab is evidence that the underlying disease in the treated patient is auto-immune.) For 4 of those 7 patients, their ME began with a viral infection (specifically mono, or glandular fever, in 3 of them). It seems to me that a viral infection must have triggered an auto-immune disease in these people.

That's not to say the infection was the sole cause of these people developing auto-immune disease. I'm sure there's also a randomness element, and maybe also a genetic factor. But the above seems to indicate that in some ME patients, the underlying pathology is an auto-immune disease that's triggered by an infection.

Your thoughts?

 

[Jonathan Edwards]

@Jonathan Edwards, here is my understanding of your position: There may be a subset of ME patients whose underlying pathology is some sort of auto-immune disease, and if so, this auto-immunity almost certainly wasn't triggered by an infection. Is that a fair characterization?

I find this hard to square with what we saw in the phase 2 open-label Rituximab trial. 7 of the 28 patients went into long-term remission after just 5-6 infusions. Because their remission was long-term, it seems like they must have an auto-immune disease and Rituximab broke the feedback loop. (I believe you have previously said that long-term remission from Rituximab is evidence that the underlying disease in the treated patient is auto-immune.) For 4 of those 7 patients, their ME began with a viral infection (specifically mono, or glandular fever, in 3 of them). It seems to me that a viral infection must have triggered an auto-immune disease in these people.

That's not to say the infection was the sole cause of these people developing auto-immune disease. I'm sure there's also a randomness element, and maybe also a genetic factor. But the above seems to indicate that in some ME patients, the underlying pathology is an auto-immune disease that's triggered by an infection.

Your thoughts?

I think we discussed this issue a bit before. The problem is that if the autoimmune process manifests itself as an inappropriately prolonged and severe response to infection, then even if the autoimmune disease is already sitting there it may first show itself when a virus comes along. So the virus may not cause the autoimmunity, it may just allow it to show itself.

Having said that it is still quite possible that this sort of ME/CFS is an exception amongst autoimmune diseases. Almost every autoimmune disease is an exception to some rule or other. And if there is going to be an infection that breaks the rules EBV is the obvious top choice since it lives in B cells.

What I think is misleading is the constant reference in immunology reviews to the idea that autoimmune diseases are often triggered by infections so if ME is autoimmune it is likely to be triggered by infection. The vast majority of autoimmune diseases show little or no epidemiological relation to infection. It is a theory without evidence. We also have the problem that people always tend to attribute illnesses to events like trauma or infection because it is human nature to blame something.

 

[greeneagledown]

We also have the problem that people always tend to attribute illnesses to events like trauma or infection because it is human nature to blame something.

That may be the case in other diseases, but I find it hard to believe that phenomenon would be relevant in ME (although that might not be your point). This disease is severe enough that I don't think it's possible for someone with sudden onset to be unsure about when it began, or to falsely attribute it to an infection when in reality they've already had ME for a while or something. People with sudden onset-ME (which is most of us) know exactly when our disease began.

 

[Jonathan Edwards]

That may be the case in other diseases, but I find it hard to believe that phenomenon would be relevant in ME (although that might not be your point). This disease is severe enough that I don't think it's possible for someone with sudden onset to be unsure about when it began, or to falsely attribute it to an infection when in reality they've already had ME for a while or something. People with sudden onset-ME (which is most of us) know exactly when our disease began.

I am sure that is true, at least for a proportion but we have to take into account the tendency of physicians to link illnesses to events too when the forms get filled in!

 

[lansbergen]

I think we discussed this issue a bit before. The problem is that if the autoimmune process manifests itself as an inappropriately prolonged and severe response to infection, then even if the autoimmune disease is already sitting there it may first show itself when a virus comes along. So the virus may not cause the autoimmunity, it may just allow it to show itself.

Did you never wonder why the UK population is not wipe out by the BSE epidemic?

TSE is an infection. Low virulent strains can (partly) protect against high virulent strains.

Prpc is self. Prpc antibody degrades Prpc. Prpc degradation slows infection progress.

Prpc antibody can (partly) protect against terminal Prpsc deseases

Prpc is an important protein. Not enough of it can cause problems.

 

[A.B.]

Prpc is self. Prpc antibody degrades Prpc. Prpc degradation slows infection progress.

Prpc antibody can (partly) protect against terminal Prpsc deseases

Prpc is an important protein. Not enough of it can cause problems.

What problems are associated with low PrPc? And what does this have to do with autoimmunity?

 

[lansbergen]

What problems are associated with low PrPc?

Prpc is an very old protein and is in (almost) every celltype. TSE agents infect immune cells first.

TSE research is a minefield. Prpc-- mice research can give different results. It took them decades to notice any abnormalities . That tells something about the researches observing skills.

Besides the Prpc gen there is a dopple Prpc gen that (partly) could substitute for the Prpc gen. .

 

[BurnA]

I think we discussed this issue a bit before. The problem is that if the autoimmune process manifests itself as an inappropriately prolonged and severe response to infection, then even if the autoimmune disease is already sitting there it may first show itself when a virus comes along. So the virus may not cause the autoimmunity, it may just allow it to show itself.

This would certainly explain why so many people associate onset with viral illness. But if this was the case - how could this be associated with autoantibodies ? Is it that the conditions are right for their production and the virus is the ignition mechanism or the autoantibodies are there but not actually doing anything sinister until the immune system gets set by an infection ?

Having said that it is still quite possible that this sort of ME/CFS is an exception amongst autoimmune diseases. Almost every autoimmune disease is an exception to some rule or other. And if there is going to be an infection that breaks the rules EBV is the obvious top choice since it lives in B cells.

Just an observation that while EBV seems to be a predominant virus related to onset it isn't exclusive, many people seem to associate colds etc with onset.

What I think is misleading is the constant reference in immunology reviews to the idea that autoimmune diseases are often triggered by infections so if ME is autoimmune it is likely to be triggered by infection. The vast majority of autoimmune diseases show little or no epidemiological relation to infection. It is a theory without evidence. We also have the problem that people always tend to attribute illnesses to events like trauma or infection because it is human nature to blame something.

Yes it is human nature to understand the cause of everything. And in the absence of a proven cause, all sorts of things will be speculated. The problem can be made worse when medical specialists propose theories without any underlying proof. Think Vitamin C and Linus Pauling.
But, there does seem to be an lot of people who associate virus with onset, in fact it appears to be one of the more consistent features of this disease. So much so, that coincidence seems less likely in my opinion.

Therefore i think the most likely explanation is indeed that the autoimmune disease is sitting there and only shows itself when a virus comes along. Are there any more details or ideas on how this could happen ?

 

[lansbergen]

And what does this have to do with autoimmunity

Natures builtin safety belt is an antibody against the self protein which serves as material for the pathogenic Prpsc. Less Prpc->less Prpsc. Prpsc is the surrogate marker for TSE.

In other words: an autoantibody decreases the risk for develping terminal TSE

 

[unto]

Jonathan Edwards said: ↑
I think we discussed this issue a bit before. The problem is that if the autoimmune process manifests itself as an inappropriately prolonged and severe response to infection, then even if the autoimmune disease is already sitting there it may first show itself when a virus comes along. So the virus may not cause the autoimmunity, it may just allow it to show itself.


@BurnA

Therefore i think the most likely explanation is indeed that the autoimmune disease is sitting there and only shows itself when a virus comes along. Are there any more details or ideas on how this could happen ?


I do not believe to cause epidemics of Lake Thaoe, at the Royal Free Hospital, in Los Angeles, Adelaide etc ......, it may have been the latent autoimmunity

 

[Jonathan Edwards]

I do not believe to cause epidemics of Lake Thaoe, at the Royal Free Hospital, in Los Angeles, Adelaide etc ......, it may have been the latent autoimmunity

I agree that seems very unlikely. But the problem is that these epidemic cases may be a different 'ME' from an autoimmune ME. They may simply be examples of viruses that themselves are capable of producing a violently overaggressive cytokine response or whatever. So that an autoimmune ME would be mimicking just that. And at the other end of the spectrum there are people whose ME seems to develop gradually stepwise over months or years. I don't think there is any one knock down answer to all cases but I agree that there is reason to think that some cases genuinely are triggered by viruses.

 

[BurnA]

Aha! And another Aha! This one paper on methylation from Monday finds hypermethylation of BCL10, which is involved in B cell proliferation, and CD23 (FcER2), which is what Jo Cambridge at UCL has been getting excited about as a marker of reactivating B cells in autoimmunity! It could be a coincidence but it would be quite hard to have a result more in keeping with what we have been discussing with the Norwegians. I am not sure this has anything to do with generalised methylation but it certainly looks interesting. It might be an easier way to identify B cell misbehaviour than just numbers.

And it looks as if there is another important collaborative group producing interesting data on ME biology I had not come across.

Just wondering if anything ever came of this - Did it lead to anything ?

 

[Eeyore]

It sounds as if nothing much happened. Antibodies to everything may rise following an immune stimulus, briefly. Antibody levels are not black and white. We all have low levels of autoantibodies. What matters is if there is a chain reaction that produces permanent high levels and clinical disease.

@BurnA

While I agree that the event was probably not significant for the individuals involved, it may very well be significant for understanding the pathogenesis of ME. Many with ME (myself included) have had severe reactions to vaccines. It appears that there is a general adjuvant effect of vaccination that upregulates the immune system and produces autoantibodies. The immune system acts as a coordinated network of signalling and effector cells and molecules.

The older belief in rheumatology/immunity was that normal people did not have autoantibodies, and if by random chance you developed autoantibodies, you got autoimmune disease. We now know this is not the case, and that antibodies against self frequently arise in healthy people. Normally, our immune systems are self regulating and those cells which are causing harm are removed, reestablishing self tolerance. I think the mechanisms of this need further elucidation, although there has been progress.

We know autoimmune diseases cluster in certain individuals, which would not be expected if they were random events. Rather, there is something abnormal about certain individuals in that they do not correctly regulate the immune system. This is probably genetic in nature. HLA's likely have some relevance in terms of which antibodies are formed (due to the peptides recognized). DR4 is more common in RA, DR3 (8.1 haplotype in particular) is common in many autoimmune diseases, etc. Beyond that though, the HLA's may often have more to do with which autoimmune disease you get. Most people with DR4 do not get RA. There are also linkage considerations - the 8.1 haplotype is associated, for example, with C4AQ0, which is known to increase the risk of SLE and a number of other diseases through impaired opsonization mechanisms.

 

[Tammy]

Just an observation that while EBV seems to be a predominant virus related to onset it isn't exclusive, many people seem to associate colds etc with onset.

EBV can present itself as cold symptoms.

 

[Eeyore]

EBV can present itself as cold symptoms.

EBV seems to be a virus that triggers ME in some people, but it's not the cause of ME, as there are people with ME who do not have EBV, and there is no significant difference in any measure of EBV in ME patients and non-ME patients.

A trigger is not the same as a cause. Most people get EBV at some point in their lives, and then live with it forever as all herpesvirus infections are lifelong in all cases. They don't generally get ME though.

It is possible that some viruses may alter the immune system in a way that make autoimmune disease more likely, and there are some studies suggesting links between EBV and MS. It's not that MS is infectious, but more likely that EBV may actually alter immune function long term. There is also evidence that CMV infection in apparently healthy people has long term effects on immune function that may be clinically relevant.