Do MEs cause CFS?

[Marco]

[quote="Bob, post: 497540, member: 558"

I think your response, above, explores what usually happens in the gut, when everything is running as it should do (i.e. in a healthy person.)

But I'm exploring the possibility of (localised or general) dysfunction of the cells lining the gut, whereby the contents of the gut might suddenly be treated as a foreign invader, for whatever reason. (Perhaps mild damage to the gut wall, or a dysfunction of the immune/protective processes within the gut? Or perhaps there could be an autoimmune issue that attacks the gut lining?)[/quote]

Hi Bob.

This paper might be of interest to you.

Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842521/

While it discusses the specific case of the gut's contribution to systemic inflammation in chronic alcohol use it does also outline more generally how a 'defect' in permeability and detox capacity may interact and many pathological findings in alcohol abuse overlap with ME/CFS (ironically)..

Nothing to do with autoimmunity though!

 

[deleder2k]

Yes, I haven't seen it before today, but it seems to be quite old. I think the document says the research proposal is from 2012. Deleder might know more about it.

Check this out guys: http://www.ncbi.nlm.nih.gov/pubmed/25115874

Nothing new on the Rituximab IBS study, or the ME/CFS Rituximab study for that matter.

 

[Marco]

@Jonathan Edwards

ME/CFS has been associated with reduced heart rate variability (frequently) and increased arterial stiffness (more than once) attributed to low grade systemic inflammation/oxidative stress.

The abstract below states that both are also frequent findings in rheumatoid arthritis which contributes to increased cardiovascular risk (presumably also as a result of the inflammatory process). It also suggests that both improve following treatment with rituximab.

http://www.abstracts2view.com/eular/view.php?nu=EULAR10L_SAT0151

Given that plausible cases have been made for the contribution of both reduced HRV and arterial stiffness to the symptoms of ME/CFS, might these measures be useful as secondary but objective output measures in ritux trials?

 

[aimossy]

Check this out guys: http://www.ncbi.nlm.nih.gov/pubmed/25115874

Nothing new on the Rituximab IBS study, or the ME/CFS Rituximab study for that matter.

Thanks for that
I am just wondering.So the study they outlined wanting to do on ritux and IBS- do you know if the study was carried out and should be published at some stage. My perception was it was a proposed study or proposal to do it - so I wasn't sure from what I read in the link that it definitely happened. Do you know deleder?
Thank you for keeping us up to date with things in Norway!

 

[Jonathan Edwards]

I'm probably asking some basic stuff that you've explained before, but do you think that many autoimmune conditions involve a proliferation of b-cells due to b-cells creating antibodies to themselves, or would that be an unusual scenario?

Also (sorry, I know you've explained this before, but I've lost the info), in relation to your explanation of the destructive process for antibodies, how does the immune system decide whether an antibody is useful or not? i.e. how does the immune system distinguish useful self-proteins from harmful foreign proteins when newly created antibodies attach themselves to proteins?

Nope, I haven't dealt with either of those. The first is fascinating. I am not sure that autoimmunity ever involves antibodies to B cells as such. What seems more likely is that it involves antibodies that bind to molecules that normally signal to B cells in some way. The precise mechanisms are complicated. However, there is one conditions in which there are specific autoantibodeies to a molecular conformation that is expressed on B cells when they are in a follicle centre - called peanut agglutinin receptor. This happens in sarcoidosis. If B cells had antibody to this on their surface they could stick to each other in follicle centres in a way that might protect them from being weeded out. The follicle centre is a bit like musical chairs. The B cells compete for attaching themselves to antigens stuck on the tissue framework cells. Unstuck cells are destroyed. Maybe sticking to each other they can survive. But this is a very speculative case.

The immune system has a very complicated set of 'checkpoints' for every B cell to go through before it is allowed to make antibody. Most B cells that express autoantibody on their surface are probably given instructions in the bone marrow right from the start to 'try again' if they seem to be sticking to self proteins. This is called receptor editing. Then a B cell is not allowed to multiply and make bulk antibody unless it can get help from T cell and T cells get weeded out on self proteins too - in their case in the thymus. There is also a rule that if a B cell sees a protein in solution (likely to be self) it is told to ignore it and die but if it sees the protein already stuck to complement fragments it should multiply. That allows the innate immune system to label foreign proteins with complement as a 'danger' signal. There are other mechanisms too but the truth is that nobody is quite sure how the system manages to get things right almost all the time because this sort of 'consensus' approach to identifying 'dangerous' proteins has lots of potential loopholes. And it seems that in autoimmunity the gossip gets around that a protein is foreign when in fact it is not. The T cells get asked but they mishear what they are being asked and say yes instead of no.

Trouble is the question needs a book to answer and even then nobody really knows exactly what's going on!

 

[Jonathan Edwards]

@Jonathan Edwards

ME/CFS has been associated with reduced heart rate variability (frequently) and increased arterial stiffness (more than once) attributed to low grade systemic inflammation/oxidative stress.

The abstract below states that both are also frequent findings in rheumatoid arthritis which contributes to increased cardiovascular risk (presumably also as a result of the inflammatory process). It also suggests that both improve following treatment with rituximab.

http://www.abstracts2view.com/eular/view.php?nu=EULAR10L_SAT0151

Given that plausible cases have been made for the contribution of both reduced HRV and arterial stiffness to the symptoms of ME/CFS, might these measures be useful as secondary but objective output measures in ritux trials?

Possibly, but I am not sure how consistent the finding is in ME and I don't think clinicians are likely to have routine access. Dr Fluge has been looking into vascular physiological measures though.

 

[Bob]

@Jonathan Edwards, thanks very much for the explanations. It's very interesting. I'm always amazed at both how much we know and how much we don't know, in medical science. If any researchers can to grips with exactly how the signalling works for B-cell destruction, then it seems to me that there might be an award awaiting.

 

[deleder2k]

Thanks for that
I am just wondering.So the study they outlined wanting to do on ritux and IBS- do you know if the study was carried out and should be published at some stage. My perception was it was a proposed study or proposal to do it - so I wasn't sure from what I read in the link that it definitely happened. Do you know deleder?
Thank you for keeping us up to date with things in Norway!

I think they are underway with it. I have no clue whether they will publish it or not.

 

[A.B.]

@Jonathan Edwards I'm curious what the poll can ultimately tell us.

If CFS/ME patients have higher than expected rates of autoimmune processes involving the thyroid, what does this mean? Conversely, what does it mean if they're lower than expected? And what are the expected rates?

Similarly for the thyroid function. Earlier you guessed that 35% would have thyroid dysfunction. According to the public responses (including people not on the list) about 50% have or had thyroid dysfunction.

 

[Marco]

Possibly, but I am not sure how consistent the finding is in ME and I don't think clinicians are likely to have routine access. Dr Fluge has been looking into vascular physiological measures though.

I can dig out the research refs. I'm not sure what the relevance is of clinicians as its very unlikely this is routinely tested. Presumably Fluge and Mella could arrange for testing if they considered it useful?

 

[Jonathan Edwards]

@Jonathan Edwards I'm curious what the poll can ultimately tell us.

If CFS/ME patients have higher than expected rates of autoimmune processes involving the thyroid, what does this mean? Conversely, what does it mean if they're lower than expected? And what are the expected rates?

Similarly for the thyroid function. Earlier you guessed that 35% would have thyroid dysfunction. According to the public responses (including people not on the list) about 50% have or had thyroid dysfunction.

The purpose of the poll for me is to get a reasonable idea of whether or not it is likely that PWME do indeed have evidence for increased frequency of thyroid related autoimmunity. It is clear that the antibody tests are not done that often but abnormal thyroid function is thought to be chiefly autoimmune in developed countries. If there is a hint that the rates are higher than expected in a normal population that increases my motivation for thinking we need a proper population based demographic study. It is no good going on reports of case records or positives in ME patients compared to lab standards. There has to be a prospective study with quantitative assessments in patients and controls done blinded. That requires money and time but nothing difficult in terms of technology. I am thinking it is needed as a minimum to get the unbiased basic data needed to study MEs at all. If we can show there is a real difference in that sort of study we have hard evidence that MEs have a biological basis - which for me is still the Holy Grail that we do not have in the way that will convince the scientific community. We had to do this in RA. It has to be done in ME if anything is to be done properly at all.

 

[MeSci]

There are other mechanisms too but the truth is that nobody is quite sure how the system manages to get things right almost all the time because this sort of 'consensus' approach to identifying 'dangerous' proteins has lots of potential loopholes. And it seems that in autoimmunity the gossip gets around that a protein is foreign when in fact it is not. The T cells get asked but they mishear what they are being asked and say yes instead of no.

I've got it! They are answering the question before last!

 

[Jonathan Edwards]

I've got it! They are answering the question before last!

Absolutely correct. Together we could write the ultimate textbook on immunology.

 

[A.B.]

If there is a hint that the rates are higher than expected in a normal population that increases my motivation for thinking we need a proper population based demographic study.

Looking at the data from the public responses (which is probably biased), 11 of 26 people (about 40%) said they tested positive for antibodies. This excludes people who said they didn't know, or were not tested for it, and of course doesn't reflect who is actually in the randomly selected list.

I'm guessing this is quite a bit higher than what is found in the normal population?

There has to be a prospective study with quantitative assessments in patients and controls done blinded. That requires money and time but nothing difficult in terms of technology. I am thinking it is needed as a minimum to get the unbiased basic data needed to study MEs at all. If we can show there is a real difference in that sort of study we have hard evidence that MEs have a biological basis - which for me is still the Holy Grail that we do not have in the way that will convince the scientific community. We had to do this in RA. It has to be done in ME if anything is to be done properly at all.

This would be the next best thing besides proper diagnostic tests and treatment. Once it is taken more seriously, everything should become easier and better. Also, it's interesting that RA was apparently not taken as seriously as it is today.

 

[Persimmon]

It is clear that the antibody tests are not done that often but abnormal thyroid function is thought to be chiefly autoimmune in developed countries. If there is a hint that the rates are higher than expected in a normal population that increases my motivation for thinking we need a proper population based demographic study. It is no good going on reports of case records or positives in ME patients compared to lab standards. There has to be a prospective study with quantitative assessments in patients and controls done blinded.

@ Jonathan Edwards
Would you please outline how such a demographic study would be conducted.

 

[Jonathan Edwards]

@ Jonathan Edwards
Would you please outline how such a demographic study would be conducted.

The methodology would require some careful thought but I am thinking in term so the Norfolk Arthritis Register in the UK. This takes a pre-defined population within a geographic area of about 500,000. There is a method for identifying cases through primary health care units backed up by research staff who document diagnostic criteria and organise collection of blood samples etc. It can be a cross sectional study at a point in time or better a longitudinal incidence study over perhaps ten years (or both). Age and sex matched controls are identified from the same population. All laboratory investigations are analysed in a single centre using the same standards without knowledge of whether they come from patients or controls. Etc. etc. Setting up a study of this sort would require significant funding either by a major charity or a government based research institution but there are a number of precedents going back to the Framingham Heart Study in 1948.

 

[Snow Leopard]

Thanks Hip. The problem with 'models of autoimmunity' in mice is that they are not in fact models of human autoimmunity. For nearly all human autoimmune diseases there is no evidence for an infective trigger.

Not all the suggestions of infection and induced autoimmunity was so much a direct cause and effect, but a risk factor eg certain viruses interfere with immune signalling which could in principle induce states where the risk of inducing autoimmunity is substantially higher. Unfortunately it is something hard to prove in humans ethically...

Eg this:
http://www.ncbi.nlm.nih.gov/pubmed/22797944

It's not the most exciting paper, but just explaining the links between particular diseases and an imparied (or exaggerated) cellular stress response. The decreased HSP findings in CFS patients is actually one of the most consient findings I've seen so far and I guess it plays in hand with the other papers showing increased oxidative stress response.

 

[Jonathan Edwards]

Not all the suggestions of infection and induced autoimmunity was so much a direct cause and effect, but a risk factor eg certain viruses interfere with immune signalling which could in principle induce states where the risk of inducing autoimmunity is substantially higher.

The decreased HSP findings in CFS patients is actually one of the most consient findings I've seen so far and I guess it plays in hand with the other papers showing increased oxidative stress response.

I remain sceptical. Autoimmunity is not influenced by general up or down pressures on the immune system as far as we can see from the maths from the epidemiology. Flu epidemics are not followed by any rise in autoimmunity. Nor is famine, war, or even surviving a 'living grave' in a Japanese prisoner of war camp, where they did controlled trials on minimum vitamin requirements for survival. Viruses induce immune signalling in terms of cytokines and other innate signals but autoimmunity is due to very specific errors in adaptive signalling. I think MeSci's Two Ronnies video is a brilliant metaphor here. You can't stop laughing, not just because Corbett is answering the question before last but because it just so happens that the answer to the question before last makes a good joke as the answer to the last question. If the questions had not happened to be in that particular order there would be no joke - i.e. no autoimmunity. From my understanding of how the adaptive response works I just do not see how a general effect on signalling would make much difference to this sort of mistake. The exception that we do know about is that appearance of autoimmunity, often transiently, after bone marrow ablation and transplantation. But in that situation you are wiping the whole system out and asking it to build an adaptive repertoire from nothing. It is perhaps not surprising that some crossed wires occur in that situation for a while.

The problem is that the lab research community take it to be a well known fact that infection triggers autoimmunity whereas this is in fact merely a well known empty speculation from fifty years ago that has never had any firm theoretical basis, nor any experimental confirmation. Science is unfortunately rather like religion. Beliefs get stuck. As someone said scientists rarely change their minds; they just die and get replaced by a new generation with new ideas if we are lucky. Most of the time unfortunately the new generation believes what their teachers said.

 

[Sidereal]

As they say, science progresses one funeral at a time.

 

[MeSci]

I remain sceptical. Autoimmunity is not influenced by general up or down pressures on the immune system as far as we can see from the maths from the epidemiology. Flu epidemics are not followed by any rise in autoimmunity. Nor is famine, war, or even surviving a 'living grave' in a Japanese prisoner of war camp, where they did controlled trials on minimum vitamin requirements for survival. Viruses induce immune signalling in terms of cytokines and other innate signals but autoimmunity is due to very specific errors in adaptive signalling. I think MeSci's Two Ronnies video is a brilliant metaphor here. You can't stop laughing, not just because Corbett is answering the question before last but because it just so happens that the answer to the question before last makes a good joke as the answer to the last question. If the questions had not happened to be in that particular order there would be no joke - i.e. no autoimmunity. From my understanding of how the adaptive response works I just do not see how a general effect on signalling would make much difference to this sort of mistake. The exception that we do know about is that appearance of autoimmunity, often transiently, after bone marrow ablation and transplantation. But in that situation you are wiping the whole system out and asking it to build an adaptive repertoire from nothing. It is perhaps not surprising that some crossed wires occur in that situation for a while.

The 2 Ronnies sketch fits quite well with the homeostatic problems I have, and suspect that others have too.

Typical example: feeling cold. A few minutes later I feel my body heating up again. But it doesn't stop heating up after getting to an optimal perceived temperature, but continues to heat up until I am red in the face, sweating and now wearing several fewer layers of clothing, consequently also exhausted from the effort of frantically tearing them off.

Is this simply an overshoot, a lack of effective and timely feedback or is my 'central heating' still responding to the previous request - to warm up?

And could anything analogous be involved with regard to causative stages as well as to symptomatology?

But something needs to be happening to create the abnormality of response/reaction in the first place.

An obvious location for such an abnormality would appear to be the HPA axis, from where major homeostatic mechanisms are controlled.

Autoantibodies here?

But why have they/their precursors not been deleted? T cells answering the wrong question(s)?

Back to where we started!

I'm just thinking online here to try to clarify things in my own head.

Please correct or confirm or clarify anything that is rubbish (or not)!