Do MEs cause CFS?

[Jonathan Edwards]

Complement activation by IgG or IgM requires at least 3 arms of C1q to be immobilised by an interaction with immunoglobulin. IgM can immobilise 5 arms at a stroke. A single IgG can only do one arm so you need 3 IgGs to activate complement and they need to be close together and in positions compatible with the steric restriction of binding - i.e. they have to be able to present C1q binding sites at 60 degree angles to each other and not get in each other's way. Each IgG has two binding sites but on opposite sides so it cannot use both to bind any single C1q. In fact you could write a book on all the steric issues for IgG3, IgG4, glycosylation variants .....

I am not sure that anything would block C1q binding but then you have to think of CD55 (?and CD46, I forget) blocking the downstream activation of C3 and C5-9. CD55 is plastered on fibrils in some tissues and not others. But ironically CD55 may facilitate FcRIII activation. And so it goes on!

 

[Snow Leopard]

Complement activation by IgG or IgM requires at least 3 arms of C1q to be immobilised by an interaction with immunoglobulin. IgM can immobilise 5 arms at a stroke.

So the next obvious question is why would we not see sustained IgM production? (and thus inflammation)

Has this been explained for something like Graves' disease for example?

 

[Jonathan Edwards]

So the next obvious question is why would we not see sustained IgM production? (and thus inflammation)

Has this been explained for something like Graves' disease for example?

Very neat question. In RA you do get sustained IgM rheumatoid factor but because the antigen is in the circulation, fixing of C1q leads to clearance, not inflammation. I am not sure about something like Grave's but some of the mechanistic models we have been using actually bypass any IgM phase. A mutation of an IgG to become an IgG autoantibody may light up further IgG production without there ever being an IgM phase. On the other hand we tend to think that persistent presence of antigen will tickle up IgM. Maybe with thyroid antigens they are very lcoal and they do not get carried to lymphoid tissue with the right danger signals. - I don't have a good answer, is what it amounts to. I will discuss it with Jo C. (Maybe its the DAF/CD55 distribution that blocks the C3d danger signal.)

 

[melamine]

My idea for ME5 is that what is in overdrive is a part of the response to virus that does not directly involve the fever mechanism. I am suggesting it involves gamma interferon but not TNF so much. Could well be wrong but that is the sort of angle. It might possibly 'pre-empt' viral symptoms by getting to work on the virus before there is a big enough burst of viraemia (virus in the blood) to trigger the usual fever signals. There might be a distant analogy here with the B27 class I allele. People with B27 get ankylosing spondylitis and Reiter's but I gather that they are the slowest to progress to AIDS if they are infected with HIV. This has led to the idea that B27 is an 'overenthusiastic' class I type.

Angela Vincent talked at the IiME conference about the ion channel antibodies that cause rare neurological diseases, some of which can look a bit like CFS. I would be very happy to put in an ME7 based on autoantibodies to muscle ion channels. I bet there is a disease like that but it might be very rare. And then of course there is the possibility that there is a functional cross talk between immune system and muscle of an unexpected kind. It is worth noting that myasthenia gravis is in a sense both a disease of muscle and a disease of thymus.

@Jonathan Edwards - this is a most interesting discussion that I am trying to catch up on. There are too many things I want to ask and respond to, but will start with this: I have some HLAs, including B27. I do not have AS, being in fact on the extra-flexible side, but became ANA positive about 5 years ago, about the time I was diagnosed with sicca syndrome. I have low levels of a variety of antibodies, but like WillowJ, do not fit into any particular autoimmune disease category, and also like her, do not mount an effective fever. I did not develop autoimmune symptoms or pattern of flares until late in the course of my post-viral disease, and only after other identifiable as well as unidentifiable insults, and a couple more major, highly unusual infections, during which I failed to mount a sufficient response in terms of fever or swollen glands, and was therefore misdiagnosed yet again. That meant I also failed to receive treatments that might have spared my immune system a LOT of stress.

As neuropathic symptoms began insidiously and have advanced over the past 15 years, particularly post- infections, ion channel research was one of the many areas I searched for a potential diagnosis. An increase in excitotoxic/neurotoxic symptoms that I experience chronically to one degree or another now, always precedes advancing neuropathy. My CK is always elevated at rest. I don't know if either of those things would suggest an ion channelopathy. No doctor has ever explained the CK and they simply don't understand the other. I found the following passage in an article on ion channel antibodies that seems to reflect my chronic muscle symptoms in a way that relates to the nervous system symptoms.

"Antibodies against voltage-gated potassium channels contribute to a broader range of autoimmune disorders, involving both the central nervous system and peripheral nervous system. In some patients with acquired neuromyotonia (NMT), also known as Isaac's syndrome, antibodies against voltage-gated potassium channels prevent membrane re-polarization, increase acetylcholine release, and prolong action potentials. The excess release of acetylcholine often leads to muscle twitching, cramps, stiffness, and abnormal muscle contraction and relaxation. Peripheral nerve hyper-excitability sometimes co-exists with effects in the central nervous system.."

...all of which seems to lend credence to some of your speculations here?

 

[boohealth]

Continued from the thread: Who tried immunosuppressive treatment/drugs.

Do MEs cause CFS?

I thought I would set up this thread to discuss two thoughts about what ‘ME’ might be. One is that there are several MEs and the other is that MEs are maybe causes, not effects – which I will deal with first.

@Jonathan Edwards Just noticed this thread and will enjoy reading it.
I would add other pathogens to the mix, not just virus. Any persistent pathogen will do to ignite a destructive response.
I also think that some of us partially clear a pathogen, but not enough. Even on ARV therapy for HIV, for instance, low levels of the virus persist, not detectable in blood, but nonetheless damaging over the years--with conesequences including earlier death etc. A pathogen not entirely cleared, and still provoking grumbles from the immune system, might be an ME leading to CFS. This reminds me of the research showing that G-CSF, an immune booster, helped sufferers of Crohn's disease, implying that it was not an over reaction entirely, but an under-response of one arm answered by the over-response of another arm of the immune system.
Whether you are going to effectively trounce and quiet that pathogen--whatever it may be--depends on your initial response to it. A highly inflammatory initial response to a pathogen is not necessarily good. It sets a curve or a longer term response that can be harmful. That's all probably due to genetic variation and luck of the draw in the pathogens you meet.

 

[lansbergen]

And how does that explain undertemperature during flares?

 

[BurnA]

The questions are beginning to get too tricky! The trouble is I think it can work both ways around. The virus may trigger a hyper-responsiveness or the hyper-responsiveness may be there waiting for the first virus to show it up. I am sceptical about some of the standard stories about infectious triggers like molecular mimicry but I have to admit that for ME viral episodes somewhere at the beginning do look as if they must be relevant to at least some subgroups.

Could you elaborate or explain a bit more the speculative ME5 if you don’t mind.

I can’t figure out, are you suggesting this is caused by a virus initially and then possibly exercise or stress drives the immune response or what role does a virus play in this ?
Also, when you talk of hyper-sensitivity, is this different to an autoimmune problem or is it the same thing?

Many Thanks.

 

[Jonathan Edwards]

Could you elaborate or explain a bit more the speculative ME5 if you don’t mind.

I can’t figure out, are you suggesting this is caused by a virus initially and then possibly exercise or stress drives the immune response or what role does a virus play in this ?
Also, when you talk of hyper-sensitivity, is this different to an autoimmune problem or is it the same thing?

Many Thanks.

Things get pretty complicated with these sorts of mechanisms and I think 'caused by a virus' is too simple. Causation is likely to involve feedback loops based on several factors - genetic, stochastic and probably environmental here. You can actually play it all sorts of ways around. What I suspect is that if this sort of mechanism occurs then it does not much matter what virus is around at the beginning of symptoms.

The idea is that once things have got started the immune system is dysregulated by the presence of antibodies that amplify the sort of cytokine or other signal responses that we usually make to viruses. Everyday activity probably stirs these up a little bit and with the antibodies present that could get amplified to seem like full blown 'flu'. So this is hyper-sensitivity of a signalling mechanism facilitated by autoantibody. Autoimmunity itself is not really a hyper-sensitivity. It is an inappropriate reaction - different from allergy which is a hypersensitivity to things that deserve a normal low level of sensitivity so to speak.

Sorry not to be clearer but to explain the detail of the theory behind this approach would take pages. The mechanism we identified for rheumatoid arthritis had 55 steps in it!

 

[BurnA]

Things get pretty complicated with these sorts of mechanisms and I think 'caused by a virus' is too simple. Causation is likely to involve feedback loops based on several factors - genetic, stochastic and probably environmental here. You can actually play it all sorts of ways around. What I suspect is that if this sort of mechanism occurs then it does not much matter what virus is around at the beginning of symptoms.

The idea is that once things have got started the immune system is dysregulated by the presence of antibodies that amplify the sort of cytokine or other signal responses that we usually make to viruses. Everyday activity probably stirs these up a little bit and with the antibodies present that could get amplified to seem like full blown 'flu'. So this is hyper-sensitivity of a signalling mechanism facilitated by autoantibody. Autoimmunity itself is not really a hyper-sensitivity. It is an inappropriate reaction - different from allergy which is a hypersensitivity to things that deserve a normal low level of sensitivity so to speak.

Sorry not to be clearer but to explain the detail of the theory behind this approach would take pages. The mechanism we identified for rheumatoid arthritis had 55 steps in it!

Thanks.
Just wondering, there seems to be a certain group of patients who lead highly active lifestyles, eg runners, cyclists, etc., who pick up a virus infection and then develop ME shortly after returning to training. This is mentioned in this video at 33:45.

Have you come accros this type and would they fit into ME5 or another type ? I realise it may be a bit vague but your thoughts and speculations are always appreciated.

 

[Research 1st]

Thanks.
Just wondering, there seems to be a certain group of patients who lead highly active lifestyles, eg runners, cyclists, etc., who pick up a virus infection and then develop ME shortly after returning to training. This is mentioned in this video at 33:45.

Have you come accros this type and would they fit into ME5 or another type ? I realise it may be a bit vague but your thoughts and speculations are always appreciated.

Yes, but we have a problem in terms of legitimacy. These people: them, you and I - never had a diagnostic test, thus they can all be irrelevant to the scientific picture of ME (not CFS, but ME).

Lets look at the variables:

Group 1:
Athletes who get CF, are 'cured of ME' by CBT and go back to the Olympic games (misdiagnosed). We don't know who is who, percentage wise.

Group 2:
Atheletic types, who get ME and never recover.


We don't know if both have CFS type 1, 2, 3. Or just group 2 has ME. Naturally Group 1 can't have ME, as they don't have inflammation of the brain/spinal cord, recover on no immunotherapy and are as good as they ever were in a short period of time.

The highly stressed burn out professional athletes who generally all fully recover claim to have 'ME' don't develop ME when you read their stories, they develop Fukuda or Oxford criteria CFS and recover by life-style adjustment, and beating depression and reducing stress. Huge difference from an inflammation of the brain/spinal cord (ME), which is what ME is and finally, the 'CFS' research shows this as does autopsy data in ME.

Rather than asking do ME's cause subsets of CFS, we should be asking is a single cause ME inside subsets of CFS, and the answer is clearly yes, if you tear up Fukuda Criteria CFS and start insisting people diagnosed with ME actually display signs of neuroinflammation and CNS damage.

With Fukuda CFS, this can never happen, hence the CDC still want Fukuda CFS. So we have a big, ongoing diagnostic disaster.

 

[BurnA]

OK i'm not sure i get your point or if it addresses my question. I wasnt necessarily talking about olympic athletes, just highly active people who might be training for a marathon or lead stressful lives or whatever. And I certainly wasnt talking about poeple who claim to recover.
All I was wondering was, does the profile of a very active person who picks up a virus, returns to their active lifestlye and then develops ME fit one of @Jonathan Edwards types of the MEs 1-6 ?

Sure there will alway be a certain percentage of previously active people in any patient population but it seems that this manifestion is not uncommon.

 

[Jonathan Edwards]

Thanks.
Just wondering, there seems to be a certain group of patients who lead highly active lifestyles, eg runners, cyclists, etc., who pick up a virus infection and then develop ME shortly after returning to training. This is mentioned in this video at 33:45.

Have you come accros this type and would they fit into ME5 or another type ? I realise it may be a bit vague but your thoughts and speculations are always appreciated.

I have not seen any data that indicate the existence of a particular subgroup who were athletic before ME/CFS. I rather doubt that physical activity would play a significant part in pathogenesis if there is an immune basis. People talk about stress and activity affecting the immune system but there is rather little evidence that it actually causes the immune system to 'crash' into a disease state as I see it.

 

[BurnA]

I have not seen any data that indicate the existence of a particular subgroup who were athletic before ME/CFS. I rather doubt that physical activity would play a significant part in pathogenesis if there is an immune basis. People talk about stress and activity affecting the immune system but there is rather little evidence that it actually causes the immune system to 'crash' into a disease state as I see it.

Thanks. I often wondered about stress and any definite link. It certainly gets a lot of mention. Also interesting that the man in the video seemed to think it a relatively common occurence (amongst PWME ) whereby an athlete might develop ME in response to training post viral infection whereas you haven't seen any data to support that.

You do mention stress and exercise in ME5, is this more as a trigger mechanism that initiates an already dysfuntional ( or hypersensitive ) immune system response rather than anything else or have I picked it up wrong ? Apologies if these are tedious questions, just trying to understand a bit more about the role of stress and exercise if there is any.

 

[Jonathan Edwards]

Thanks. I often wondered about stress and any definite link. It certainly gets a lot of mention. Also interesting that the man in the video seemed to think it a relatively common occurence (amongst PWME ) whereby an athlete might develop ME in response to training post viral infection whereas you haven't seen any data to support that.

You do mention stress and exercise in ME5, is this more as a trigger mechanism that initiates an already dysfuntional ( or hypersensitive ) immune system response rather than anything else or have I picked it up wrong ? Apologies if these are tedious questions, just trying to understand a bit more about the role of stress and exercise if there is any.

I was really just referring to the fact that exercise leads to cell turnover with recruitment of signalling systems normally (why you wake up stiff the day after a very vigorous day before). I would have used stress in the sense of physical stresses like severe cold or maybe minor injury or whatever rather than stress in the sense of a response to threat. I'm not sure I would even use the word trigger here. The idea is that normal everyday repair signalling may be amplified by autoantibodies perhaps with recruitment of specific mediators like FcR1.

 

[A.B.]

I was really just referring to the fact that exercise leads to cell turnover with recruitment of signalling systems normally (why you wake up stiff the day after a very vigorous day before).

Could it potentially explain why someone wakes up feeling very sick and weak despite sleeping normally in every way? Especially after doing more than usual (with usual activity level being in the ME/CFS range).

 

[Jonathan Edwards]

Could it potentially explain why someone wakes up feeling very sick and weak despite sleeping normally in every way? Especially after doing more than usual (with usual activity level being in the ME/CFS range).

I think that was the logic - it's a long time since I posted those ideas!

 

[A.B.]

I think that was the logic - it's a long time since I posted those ideas!

So the general idea is that in ME/CFS there is abnormally high cell death related to exertion, and we only feel that the next day when the body has gone through maintenance routine during sleep. That would make sense to me.

Could this also explain reactions that are delayed by more than one day?

 

[BurnA]

What I suspect is that if this sort of mechanism occurs then it does not much matter what virus is around at the beginning of symptoms.

The idea is that once things have got started the immune system is dysregulated by the presence of antibodies that amplify the sort of cytokine or other signal responses that we usually make to viruses. Everyday activity probably stirs these up a little bit and with the antibodies present that could get amplified to seem like full blown 'flu'.

Ok, but does it require some virus ( any ) to be around at the start ?

And by everyday activity amplifying things to seems like flu, are you referring to the symptoms that PWME experience after over exerting themselves and experiencing flu like symptoms the next day or two ?

 

[Eeyore]

People talk about stress and activity affecting the immune system but there is rather little evidence that it actually causes the immune system to 'crash' into a disease state as I see it.

@Jonathan Edwards - One of the more clearly defined effects of exercise on the immune system is an increase in complement C4a (the cleaved, inactive part of C4 after it is activated by either C1qr2s2 or via the MBL pathway).

C4a has been found to be elevated very often in ME as well as in "chronic" (post?) lyme syndrome. It's also found in SLE. It is an anaphyotoxin. It also activates mast cells, which have been at times implicated in ME. The idea of mast cell activation logically should lead one to at least consider complement activation.

I have some strong suspicions about involvement of the complement pathways in ME. I think it would be interesting to test ME patients for circulating immune complexes.

C1-Inh deficiency leads to excessive complement activation, including complement C4. One treatment is androgen therapy - so in theory men might be less affected. However, we don't (to the best of my knowledge) see classic hereditary angioedema, which would be expected.

Personally, I do have elevated C4a. Dr. Shoemaker wrote about this a lot, and I think his clinical observations may be correct, but disagree with his (imo) oversimplification of ME as a mold exposure illness. At one point, over a decade ago, a rheum I saw was contemplating a diagnosis of Behcet's, but ultimately didn't think I really fit.

Lots of speculation here of course... just brainstorming.

 

[Marco]

I have not seen any data that indicate the existence of a particular subgroup who were athletic before ME/CFS. I rather doubt that physical activity would play a significant part in pathogenesis if there is an immune basis. People talk about stress and activity affecting the immune system but there is rather little evidence that it actually causes the immune system to 'crash' into a disease state as I see it.

Some time ago I came across one source that stated increased incidence of 'CFS' in elite cyclists (plural) with onset even occuring many years after quitting competitive cycling. Unfortunately I can only find this single case study abstract that attributes physiological changes to deconditioning (although an alternative explanation might be that improved CFS symptoms might be in response to continued abstinence from training :

The case history of an elite ultra-endurance cyclist who developed chronic fatigue syndrome.

http://www.ncbi.nlm.nih.gov/pubmed/9741601

Perhaps more interesting is this review (full paper) of overtraining syndrome/over-reaching in endurance athletes where the author refers to the parallels with CFS :

Overtraining effects on immunity and performance in athletes

The paper discusses various immune changes in athletes whether they do or don't develop overtraining syndrome although the clinical significance of the changes are debateable. One mechanisms is proposed thought whereby chronically elevated pro-inflammatory cytokines may provoke 'neuroendocrine dysfunction'.

http://www.nature.com/icb/journal/v78/n5/full/icb200070a.html