Do MEs cause CFS?

[Jonathan Edwards]

So are there any other tests that can be run to show that the ANA is due to an autoimmune illness?

Is there anything else that can cause these ANA readings?

Are there no immune regulators that are used in other autoimmune conditions that may have an effect? Like immuran that my brother uses for his crohns.

The ANA is not due to the illness. An illness may be due to the ANA. All ANAs are produced as 'immune mistakes' and being against self are 'autoimmune'. The question is whether that autoimmune antibody production goes on to cause an illness, i.e. tissue damage as in lupus or whether it causes no trouble. Autoantibodies do not necessarily cause any trouble. Quite a ot of normal people have rheumatoid factor antibodies that cause no inflammation.

So to see if an ANA is causing an illness the main thing is to see if there are symptoms, but it is also important to test for effects that might be silent like anaemia or low platelets or kidney malfunction.

There are several drugs that have some effect on reducing problems from autoantibodies, like imuran (azathioprine) but they do not work for all autoimmune problems by any means. (Crohn's disease is not necessarily autoimmune, it is what people tend to call autoinflammatory.) These drugs also have long term side effects. Imuran has been tried for ME without obvious benefit, and the same applies to steroids.

 

[user9876]

The one environmental antigen we do know gets caught up in autoimmunity is gluten in coeliac disease and it looks nothing like anything self. It drives an autoantibody response because it binds to the autoantigen, not because it looks like the autoantigen. I suspect that is true for virtually all molecules that drive autoimmune loops.

I was wondering if the generation of the antibody could be at random but it only has a noticeable effect as the body switches into a 'sick mode' after an infection. I was thinking some increase in a chemical that binds to the antibody or a change in a receptor. There would also need to be a loop maintained to keep this active and hence get the chronic behavior. That would then allow a random antibody production but an apparent viral trigger.

 

[Jonathan Edwards]

I was wondering if the generation of the antibody could be at random but it only has a noticeable effect as the body switches into a 'sick mode' after an infection. I was thinking some increase in a chemical that binds to the antibody or a change in a receptor. There would also need to be a loop maintained to keep this active and hence get the chronic behavior. That would then allow a random antibody production but an apparent viral trigger.

Yes, that is more or less the thinking I was following. There are various ways to juggle it around but these would be the key components.

 

[MeSci]

This is the old 'molecular mimicry' idea that if you think about it hard enough makes no sense. Something in a pathogen that looks like self is more likely to be ignored. It is things that look like something different that are likely to trigger reactions. There are literally tens of thousands of papers like this. People have been looking for this peptide overlap for forty years, apparently unaware that they are looking for something that would explain nothing. But unfortunately that is the way mainstream science often goes.

The one environmental antigen we do know gets caught up in autoimmunity is gluten in coeliac disease and it looks nothing like anything self. It drives an autoantibody response because it binds to the autoantigen, not because it looks like the autoantigen. I suspect that is true for virtually all molecules that drive autoimmune loops.

Thanks for that very clear explanation.

I understand that peptide overlaps have been found, e.g. see this post, from which I quote:

The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide fromChlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

I fully take on board your statement that autoantibody generation is random/stochastic, and that it is the failure to delete inappropriate antibodies that is behind autoimmunity.

So...

Could it be that, IF there are indeed relevant overlaps between an inappropriate (auto-) antibody and a pathogen, the mistake is made in reverse to the usual 'molecular mimicry' paradigm: there is something that says "No - don't destroy me - I am an antibody to a pathogen"? Or perhaps the sequence that binds to our own cells is somehow masked until something (on our cells?) unmasks it and binding occurs? Or the pathogen itself has bound to our cells so that when the autoantibody sees the cell it binds to the pathogen and this facilitates (further?) pathology?

That last bit may be garbage but brain fog has set in, so I thought I have better leave it in case it makes sense! I can't even follow it myself now...

 

[Marco]

@Jonathan Edwards

Apologies if you've already commented on the Haukeland sub-study measuring endothelial (dys)function in the Rituximab trial as mentioned here :

http://forums.phoenixrising.me/inde...ted-dilation-and-skin-microcirculation.32540/

Just wondering what you think of this. A general marker of 'disease' or something more specific?

 

[Jonathan Edwards]

Could it be that, IF there are indeed relevant overlaps between an inappropriate (auto-) antibody and a pathogen, the mistake is made in reverse to the usual 'molecular mimicry' paradigm: there is something that says "No - don't destroy me - I am an antibody to a pathogen"? Or perhaps the sequence that binds to our own cells is somehow masked until something (on our cells?) unmasks it and binding occurs? Or the pathogen itself has bound to our cells so that when the autoantibody sees the cell it binds to the pathogen and this facilitates (further?) pathology?

That last bit may be garbage but brain fog has set in, so I thought I have better leave it in case it makes sense! I can't even follow it myself now...

It is not easy at all to think this through, I agree. I do not think there are signals for 'don't destroy me - I am an antibody to a pathogen'. I think there are two sorts of signal:
1. Don't destroy me - I am making an antibody to something around here.
2. Override signal - do destroy me after all because that something is self.

Autoimmunity seems to need signal 2 to be blocked - that is all, because 'self' is around here all the time. Blocking of signal 2 must be very rare in the scheme of things because there will be millions of pathogen antigens that are almost identical to self ones and we do not get autoimmunity to all these. And autoimmunity is the same the world over, despite there being different pathogens in different climates.

But let us say a B cell that recognises self is born and signal 2 is blocked. What would that mean. It would mean that the B cell is not destroyed. Moreover, since self is around all the time and continues to be around however hard the B cell tries to make antibodies to it (unless the tissue is destroyed as in Hashimoto's), this B cell will survive and proliferate indefinitely. Notice that the presence of a pathogen looking like self does not even come into this. It is completely redundant to the theory. You do not make antibody to pathogen and then oops! discover it binds to self as well. You make antibody and if it binds to self and signal 2 is blocked you did not need the pathogen to be there. As we said in the beginning it is not the presence of the pathogen that tells the B cell to make a certain antibody. The B cell has to make that by tossing a coin and hoping it binds to something around here.

There are more complicated details about 'tuning up' antibodies by further mutations but in the end I think the same rules apply. All immunologists know these rules but many of them do not seem to think them through.

 

[Jonathan Edwards]

@Jonathan Edwards

Apologies if you've already commented on the Haukeland sub-study measuring endothelial (dys)function in the Rituximab trial as mentioned here :

http://forums.phoenixrising.me/inde...ted-dilation-and-skin-microcirculation.32540/

Just wondering what you think of this. A general marker of 'disease' or something more specific?

I am not sure what to make of this yet. It is very interesting but I would like to see how it pans out.

 

[Marco]

I am not sure what to make of this yet. It is very interesting but I would like to see how it pans out.

Yes it would be great to have some objective measures of treatment response but they would only be meaningful or at least interpretable if directly relevant to the proposed disease process or symptoms.

The only study I'm aware of that provides direct evidence of endothelial dysfunction is the farly recent Newton et al one :

http://niceguidelines.files.wordpress.com/2011/12/large-and-small-artery-endothelial-dysfunction.pdf

But there's more consistent evidence of autonomic dysfunction for example which can also be objectively measured.

I wonder what they're thinking?

Endothelial dysfunction associated ischemia/cerebral hypoperfusion would certainly bother microglia though?

Strangely enough (or not) there's a 'vascular hypothesis' of alzheimers's disease :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819581/

 

[MeSci]

Strangely enough (or not) there's a 'vascular hypothesis' of alzheimers's disease :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819581/

Not so strange - or new. I looked at this for my Masters degree over 10 years ago in a poster presentation called 'Alzheimer's and vascular dementia - a false dichotomy?', starting from the work of de la Torre et al and their 'CATCH' hypothesis. Ignore the animal stuff - just note that:

..cerebral hypoperfusion is one of the earlier (if not the earliest) clinical manifestations in both the sporadic and familial forms of Alzheimer's disease. In addition, therapy that improves or increases cerebral perfusion is generally of some benefit to Alzheimer patients.

That paper is from the year 2000!

I was struck by the substantial overlaps between so-called Alzheimer's and vascular dementia, including the fact that researchers could not agree on which condition patients had, even post-mortem. 'Vascular dementia' patients often had amyloid plaques, and 'Alzheimer' patients had cerebrovascular pathology. This has been borne out by the failure of treatments aimed at eliminating amyloid plaques to show any clinical benefits despite decades of research on this in animal 'models'. This came as no surprise to me, having critiqued these too.

Sorry - have gone O-T again. @Marco started it!

 

[Marco]

Not so strange - or new.

Sorry - I thought I was being 'arch'. Hard to get across sometimes online.

 

[MeSci]

Sorry - I thought I was being 'arch'. Hard to get across sometimes online.

Doesn't work with Aspies or borderline Aspies - we read everything literally!

And PR is positively infested with us.

 

[Marco]

Doesn't work with Aspies or borderline Aspies - we read everything literally!

And PR is positively infested with us.

Including me - and according to the online tests and my wife borderline is an understatement

 

[Helen]

I am afraid to say that I am sceptical about this sort of biochemical discussion. Do we have data from blinded trials of B12 and folate in ME? I think not. Without that my instinct is to think that PWME feel better after taking vitamins for the same reason that millions of other people feel better after taking vitamins - probably nothing to do with needing vitamins. And the various changes you suggest might relate to glutathione I cannot think will actually make any significant difference to basic metabolic pathways, except pregnancy which changes everything so we could blame anything else just as much.

I fear all the talk of B12 sounds like using scientific language without any true grasp of what would actually happen in reality. Long ago I learnt only to believe an effect where you had a quantitative 'dose-response' type relation. A theory that predicts something goes up is pretty useless. A theory that predicts something will go up somewhere between 0.35 and 0.45 units with a dose of 60mg and 0.75-0.85 units with 90mg is worth testing. Show me a glutathione dose response curve in a blinded trial of vitamins in ME patients and I will take note.

I hate to sound a spoilsport in regard to suggestions from patients, particularly as so many insightful comments come up on PR. But I have to stick to Spock mode and be dispassionate about all the theories around. We want the right answer. Methylation does not add up to me, at least so far.

Thank you Prof. Edwards for your comments. I do appreciate them, and I realize that my post seemed blurred. It was not my purpose to have any kind of biochemical discussion. I just wanted to give some kind of background to my question about possible , similar dramatic effects of B12 and folates for quite a few in other patient groups. You might have read some witnesses in the board from PWME like in this thread http://forums.phoenixrising.me/index.php?threads/toxic-homes-i-would-never-have-believed-it-important.32594/

As you point out there is no blinded study of the use of B12 and folate in ME. There is one ongoing study at the Open Medicine Institute http://forums.phoenixrising.me/index.php?threads/omf-omi-b12-folate-clinical-trial.26819/
http://www.openmedicinefoundation.org/ways-of-giving/current-funding-campaigns (sorry I couldn´t find any better presentation) and one study completed at another clinic, not yet published so I don´t know how any of them where designed. Hopefully we in a near future at least will get a better understanding of the possible impact of MTHFR-mutations and the need for B12 and folate in PWME. And if MTHFR mutations are more prevalent in PWME than in a healthy population.

For what it´s worth Nathan and Van Konynenburg conducted a clinical study on a so called methylation protocol where B12 and folate where the main supplements.
http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf
They were well aware of its limitations, but hoped it could serve as a pilot study before further and correct scientifically investigations could be conducted at a clinic with full legitimacy for doing medical research (according to personal communication with RVK).

 

[Hip]

I am afraid to say that I am sceptical about this sort of biochemical discussion. Do we have data from blinded trials of B12 and folate in ME? I think not. Without that my instinct is to think that PWME feel better after taking vitamins for the same reason that millions of other people feel better after taking vitamins - probably nothing to do with needing vitamins. And the various changes you suggest might relate to glutathione I cannot think will actually make any significant difference to basic metabolic pathways, except pregnancy which changes everything so we could blame anything else just as much.

I do not myself derive any noticeable benefit from taking vitamin B12 injections, so I cannot personally vouch for their efficacy in ME/CFS. But my understanding is that several ME/CFS doctors sometimes use B12 injections to treat their patients (doctors such as Dr Lapp, Cheney, Levine, DeMeirleir, and GP Sarah Myhill in the UK). There's some info on these doctors' B12 protocols here. The fact that some doctors use B12 is not of course the same as having good evidence from a blinded trial; perhaps such a trial might be worth undertaking.


The nearest thing to a double-blinded trial of B12 for ME/CFS I could find is this paper:

A pilot study of vitamin B12 in the treatment of tiredness

OK, tiredness is not ME/CFS, but this study does indicate that B12 can fight fatigue as a symptom.

As to its mechanism, who knows. It may have nothing to do with methylation. Indeed, I think B12 was being used on its own as a treatment for ME/CFS long before the idea of boosting methylation came along.

My guess is that B12 may benefit some ME/CFS patients by reducing the neurotransmitter glutamate, elevated levels of which having been proposed as a cause of ME/CFS cognitive symptoms. This study found that B12 inhibits glutamate release. But of course this is just pure speculation, like so many things in ME/CFS.

 

[Hip]

This is the old 'molecular mimicry' idea that if you think about it hard enough makes no sense. Something in a pathogen that looks like self is more likely to be ignored. It is things that look like something different that are likely to trigger reactions.

That principle certainty make a lot of sense.

This brings to mind a paper I glanced at a few years ago (alas I can't find it now), which was about the idea that an infection may precipitate autoimmunity when it is located a long distance from the lymph nodes (or thymus or bone marrow, I cannot remember which now).

The idea was that that as lymph nodes / thymus / bone marrow are responsible for mediating immune tolerance, if an infection is located in a place in the body quite remote from the lymph nodes / thymus / bone marrow, then any autoimmune response (instigated by antigens present in the pathogen that look like self ) may not be adequately countered or deleted by the immune tolerance mechanisms. In other words, autoimmunity may arise when the physical locations of the immune tolerance mechanisms are too remote from the infection, so they cannot properly counter an immune response on self.

I wish I could find that paper; it painted autoimmunity as resulting from a dynamic imbalance of immune response and immune tolerance.

Presumably any stagnation of lymph fluid could increase the effective distance between an infection and the lymph nodes. (Osteopath Raymond Perrin thinks ME/CFS involves lymph circulation stagnation†).

Could such a dynamic imbalance mechanism circumvent the overall principle you mentioned above?

 

[Jonathan Edwards]

That principle certainty make a lot of sense.

This brings to mind a paper I glanced at a few years ago (alas I can't find it now), which was about the idea that an infection may precipitate autoimmunity when it is located a long distance from the lymph nodes (or thymus or bone marrow, I cannot remember which now).

The idea was that that as lymph nodes / thymus / bone marrow are responsible for mediating immune tolerance, if an infection is located in a place in the body quite remote from the lymph nodes / thymus / bone marrow, then any autoimmune response (instigated by antigens present in the pathogen that look like self ) may not be adequately countered or deleted by the immune tolerance mechanisms. In other words, autoimmunity may arise when the physical locations of the immune tolerance mechanisms are too remote from the infection, so they cannot properly counter an immune response on self.

I wish I could find that paper; it painted autoimmunity as resulting from a dynamic imbalance of immune response and immune tolerance.

Presumably any stagnation of lymph fluid could increase the effective distance between an infection and the lymph nodes. (Osteopath Raymond Perrin thinks ME/CFS involves lymph circulation stagnation†).

Could such a dynamic imbalance mechanism circumvent the overall principle you mentioned above?

I think the paper may best be forgotten! Adaptive immune cells are never generated at the site of infection itself. They are generated in thymus and bone marrow and for B cells are modified in lymph node and spleen. However near or far away an infection is, has no effect on selection of adaptive cells - the antigen has to be brought to the sites of selection by dendritic cells and macrophages. In fact I know of no evidence for loss of tolerance of T cells. The religious belief in immunology is that 'loss of tolerance' starts with T cells going wrong and then B cells follow suit but all the examples we know of where that could be tested for nobody has ever found loss of tolerance in the T cells - in fact they have found clear evidence of none. As far as I understand it loss of tolerance only applies to B cells and B cells do not normally even get to the site of infection - it is their antibodies that get there.

The literature is full of these theories of how many autoreactive T cell angels can dance on a pin head and it is about time people woke up the fact that they do not exist! (At least with some possible exceptions for genetic thymic defects and endocrine diseases.) And the point remains that any theory of autoimmunity that makes use of an infective trigger actually works just as well without the infective trigger so is an unnecessary theory (to my mind at least).

 

[lansbergen]

Any known autoimmune diseases with prominent processus xiphoideus pain? Only the bottum of the xiphoid
not the rest of the sternum.

Any autoimmune diseases affecting the pleura?

Clue? Several animals had transient pericarditus.

 

[Jonathan Edwards]

Any known autoimmune diseases with prominent processus xiphoideus pain? Only the bottum of the xiphoid
not the rest of the sternum.

Any autoimmune diseases affecting the pleura?

Clue? Several animals had transient pericarditus.

Xiphoid pain not, I think.

The pleura and pericardium are specific targets for small immune complexes, as are joints, so the two tend to go together. Pleural and pericardial involvement in RA and lupus is very common - in RA it may be 20% evident clinically and considerably higher subclinically.

 

[lansbergen]

The pleura and pericardium are specific targets for small immune complexes, as are joints, so the two tend to go together. Pleural and pericardial involvement in RA and lupus is very common - in RA it may be 20% evident clinically and considerably higher subclinically.

It is not in joints but on the outside and on long bones (arm and leg) and flat bones ( shoulderblade, ribs). Any autoimmune diseases targeting periosteum?

 

[Jonathan Edwards]

It is not in joints but on the outside and on long bones (arm and leg) and flat bones ( shoulderblade, ribs). Any autoimmune diseases targeting periosteum?

Autoantibodies could in theory target anything but the common autoimmune disorders do not go for periosteum. What does go for periosteum is spondarthropathy - which includes Reiter's syndrome, psoriatic arthropathy and colitic arthropathy.