Do MEs cause CFS?

[Jonathan Edwards]

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)!

I think you are asking the right questions.

It's very complicated but it seems that in order to be clever and flexible the adaptive immune response needs to make use of 'danger signals' as well as just weeding out immature cells that see 'self'. Something I see as important is that of about 10,000 proteins we could make autoantibodies to, this only happens often for about 50 proteins and many of these proteins are themselves danger signal molecules, or involved in danger signalling.

Antibodies have two arms so they can 'cross-link' proteins to form clusters or complexes. A protein X may be seen as foreign if it has a danger signal stuck to it. But what if an antibody recognised and stuck to a danger signal? And it gets worse because antibodies are themselves important danger signals. So we get danger signals sticking to each other back to front and upside down if we are not careful..

One probably upshot is that the immune system can say 'this must be foreign because it has antibody stuck it and it would only have antibody stuck to it if previously it had been recognised as foreign' - sort of the question before last again. This seems like a dangerous way for the immune system to think but it has the advantage that it forms the basis for a chain reaction of antibody production stimulating more antibody production when a pathogen has arrived.

If this is right we would expect the immune system to have developed signalling systems to damp down any mistakes and it very much looks like these are there. B cells have receptors on there surface that look as if they are there to say 'whoa, hang on a minute, not too fast, there is already too much antibody about'. And in fact there is a mechanism called activation induced death that seems to be there to ensure that any cell that gets too manic commits suicide.

And if antibody production is based on a random sequence generator at the start, as it is, it seems to me that it is not too surprising that the system crashes quite by chance now and again.

 

[Marco]

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.

What if the paper has it a**e about face in proposing a multi-hit model involving autoimmunity, cellular stress and viruses?

I think Prof Edwards mentioned before that heat shock proteins have been associated with many autoimmune diseases but not in any specific way that wouldpoint to pathogenesis. But what if a randomly generated autoimmune process was directed specifically at HSP production?

You might expect elevated levels of oxidative stress but in normal circumstances and with a normal (brain) immune response no symptoms may be apparent. Suppose then that you encounter one of the common viruses (a la the Dubbo studies). In the absence of the protective HSP production, the immune response to the virus may be exaggerated with elevated and prolonged oxidative stress - which is of course a danger signal likely to activated the brain resident glia. A sustained exaggerated gliosis may then leave the brain primed to overreact to any subsequent oxidative stress - which with impaired HSP production is likely to result from any even minor stressor.

Such a scenario might also explain the 'non-viral' gradual onset cases and cases following a pattern of strenuous exercise. The constant repeated exposure of glial cells to the danger signals of elevated oxidative stress may similarly push the glia to a primed overreactive state?

 

[Snow Leopard]

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.

Has this study ever been done?

I mean there are all sorts of small scale studies of patient groups, which suggest high rates of infection prior to development of an autoimmune condition. Coincidence? Who knows.

It is fair to be skeptical, but I'm not convinced that the work (eg population cohort based study) to rule out the possibility has actually been done. Well, I looked and I couldn't find such a study, but I could be in error.

I wonder if the quality of the available data (eg specific questions, frequency of reporting etc) on longitudinal cohorts permits it?

 

[Bob]

@Jonathan Edwards, exploring your thoughts about the nature of autoimmunity.
ME often starts, or is perceived to start, with a stress-event (e.g. a viral infection, a vaccination, travel abroad, a period of intense physical stress, a gut or sinus infection etc.) The immune system is most active at such times, so do you think there is a higher chance of a fault occurring in the immune system at such times?

Speculating, if the fault in the immune system occurs during a period of low immune activation (i.e. not during an obvious infection), might this potentially have a higher chance of leading to gradual-onset ME, whereas a viral trigger (or perceived viral trigger) might be more likely to precipitate sudden-onset ME (or a perceived sudden onset)?

I mean there are all sorts of small scale studies of patient groups, which suggest high rates of infection prior to development of an autoimmune condition. Coincidence?

I don't think I was aware of this. Are many autoimmune conditions thought to often occur after infections?

 

[Jonathan Edwards]

Has this study ever been done?

I mean there are all sorts of small scale studies of patient groups, which suggest high rates of infection prior to development of an autoimmune condition. Coincidence? Who knows.

It is fair to be skeptical, but I'm not convinced that the work (eg population cohort based study) to rule out the possibility has actually been done. Well, I looked and I couldn't find such a study, but I could be in error.

I wonder if the quality of the available data (eg specific questions, frequency of reporting etc) on longitudinal cohorts permits it?

You wouldn't really 'do a study' here. You look at the epidemiological data that has been collected over the last century and apply logic, as Stastny did and any of us can do. I think it is useful to compare Reiter's syndrome, which is quite clearly triggered by infection, and rheumatoid arthritis, which is almost certainly not. Reiter's syndrome is not autoimmune, in the sense that nobody has ever found an anti-self response.

Reiter's syndrome was in fact first reported by Engelman, as an epidemic. Reiter reported another epidemic on a troop ship where the soldiers all had dysentery - probably shigella. Since then epidemics have been of a rather different sort - most of the patients I saw came to me in about September having met new sexual partners on Spanish beach holidays in July and acquired another intracellular triggering agent - chlamydia.

Logic tells us to expect a disease based on genetics (for Reiter's it is HLA B27 or B7) and infection is likely to occur rather predictably at the earliest age you are likely to meet the infection. For Shigella that was for troops going to Africa. For chlamydia it is 18-25. Reiter's does occur after that but I would say 80% of cases are in young adults now. As for the troops, if the infection is something people do not often encounter one might expect the age of onset to go on into middle life (as for the soldiers it did) but it really ought to become less common in the elderly who tend not to travel any more. Where we know about infective triggers the pattern fits pretty reliably.

RA, in contrast, has a pattern of incidence that has been documented over populations of millions over many decades and does not look like this at all. It is rare in children but gets going after puberty and gradually becomes commoner and commoner in incidence as you get older right up to the age of 80, when it tails of slightly. So we are looking for a mechanism that gets more likely with time, and to make it more convincing we want to explain why it goes down at 80.

An interesting fact is that breast cancer is the same - it gets commoner as women get older but then tails off at 80ish. And there is a good mathematical explanation that covers both RA and breast cancer. This is a situation where incidence depends on a variable dose of genetics (known for both) and a 'multiple hit' random component (known for breast cancer in the form of multiple somatic mutations). Multiple hit random mechanisms should tend to get commoner with time - enough time to maximise the chances of multiple hits. But if the genetic risk is high enough, as for some breast cancer risk genes, then the time needed to get the hits may be quite short. A few women are born with an almost 100% chance of breast cancer - even on both sides - by the time they are sixty. What this means is that by 80 a proportion of the cases that were going to happen will have been pretty sure to happen by then. So the maths predicts a slight tail off.

So it seems reasonable to suggest that RA is due to genes plus a random multiple hit mechanism. We know the genes and we can probably track the hits. Studies of healthy people have shown that those that will get RA later acquire autoantibodies stepwise over a 5-10 year period. Each antibody represents a bunch of somatic mutations, just like breast cancer, so it seems to fit very well.

Another well studied aspect is time of onset in identical twins - which for both RA and rbreast cancer is all over the place - quite uncorrelated. If there was an external trigger you would expect some correlation, at least if the twins remained in an environment with the same infection risks.

But what about other autoimmune diseases? None of the others are so well documented, with the possible exception of type I diabetes. Type I diabetes may indeed be the one autoimmune condition (if it really is one, and that is not entirely clear) that is commonly precipitated by infection because it is common in childhood. Very few other true autoimmune diseases are. I am not aware of good studies indicating that other autoimmune conditions are triggered by infection. Retrospective information about infection or life events at disease onset is known to be no use. People always attribute their diseases to life events, even if they have forgotten that the sequence is the wrong way around!

This sort of analysis never 'rules out' anything at a stroke. On the other hand the weight of epidemiological data for RA is easily enough to say that an infective trigger of any sort one can conceive of in the ecosystem we know we occupy simply does not fit the epidemiological facts. If you look at an incidence graph for RA and try and think how you would get that from an infective trigger it just doesn't work - unless you propose the infection alters T cell repertoire decades before the symptoms appear - i.e. in infancy. There is in fact one paper suggesting that RA risk goes up if as a young child you have a cat sleeping on your bed, but nobody has ever confirmed it!

 

[Jonathan Edwards]

ME often starts, or is perceived to start, with a stress-event (e.g. a viral infection, a vaccination, travel abroad, a period of intense physical stress, a gut or sinus infection etc.) The immune system is most active at such times, so do you think there is a higher chance of a fault occurring in the immune system at such times?

Speculating, if the fault in the immune system occurs during a period of low immune activation (i.e. not during an obvious infection), might this potentially have a higher chance of leading to gradual-onset ME, whereas a viral trigger (or perceived viral trigger) might be more likely to precipitate sudden-onset ME (or a perceived sudden onset)?

Yes. ME seems much more related to infective symptoms at time of clinical onset than other autoimmune conditions. Interestingly, however, there does not seem to be a good reason for an autoantibody being more likely to be made at such a time. The system is busier growing up anti-microbe B cell clones but as far as I know the rate of generation of new B cells, each with its randomly allocated antibody, is the same is usual. There are possible arguments for a state of active clonal expansion assisting autoimmune B cells from also expanding but they are vague and t my mind unconvincing.

If an anti-viral response does trigger autoimmunity the one expect it to produce sudden onset but the problem is that there is no way of knowing. People with RA who have been brewing autoantibodies for years may have a sudden onset when the last mutation clicks into place. Moreover, the first symptoms of joint pain may be set off by a coincidental viral infection that revs up all the B cell clones already there - something we call an anamnestic response which is well recognised.

It is indeed all speculation but I have to keep banging on about the fact that talk of infective triggers in autoimmunity is almost always based on empty dogma and it constantly needs countering. Spending another fifty years looking for infections that are irrelevant seems to me to be the wrong way to use our resources! It seems to make sense on a simplistic analysis but nobody ever cracked a disease with a simplistic analysis. Nature is subtle. But she is not vindictive so if you think carefully you can find the right answer.

 

[Bob]

Thank you, Jonathan.

People with RA who have been brewing autoantibodies for years may have a sudden onset when the last mutation clicks into place.

Sorry, this must be really basic undergraduate stuff for you, but when you say 'mutation' in relation to RA, what are you referring to?

Edit: ah, I think you've answered this in your previous post, which I'm only just reading:

Each antibody represents a bunch of somatic mutations, just like breast cancer, so it seems to fit very well.

Moreover, the first symptoms of joint pain may be set off by a coincidental viral infection that revs up all the B cell clones already there - something we call an anamnestic response which is well recognised.

So perhaps sudden-onset ME could be the equivalent of the 'anamnestic response' that you refer to in relation to RA?

 

[Bob]

There is in fact one paper suggesting that RA risk goes up if as a young child you have a cat sleeping on your bed, but nobody has ever confirmed it!

That sounds very similar to a lot of the unhelpful CFS/ME papers that are published, except usually for ME it's to do with supposed psychological flaws, or childhood trauma, rather than cat ownership!

 

[MeSci]

Thank you, Jonathan.

Sorry, this must be really basic undergraduate stuff for you, but when you say 'mutation' in relation to RA, what are you referring to?

Edit: ah, I think you've answered this in your previous post, which I'm only just reading:

Each antibody represents a bunch of somatic mutations, just like breast cancer, so it seems to fit very well.

I was going to ask about somatic mutations too. Found a definition here:

A change in the genetic structure that is neither inherited nor passed to offspring.

Foggy brain is impairing comprehension at the mo so will have to read some of these posts again.

 

[Jonathan Edwards]

That sounds very similar to a lot of the unhelpful CFS/ME papers that are published, except usually for ME it's to do with supposed psychological flaws, or childhood trauma, rather than cat ownership!

Ah but somebody thinks they have identified the commensal bacterium in cats that might get passed on the pillowcase to the child. Trouble is I cannot remember its name.

 

[Jonathan Edwards]

Thank you, Jonathan. Sorry, this must be really basic undergraduate stuff for you, but when you say 'mutation' in relation to RA, what are you referring to?

Edit: ah, I think you've answered this in your previous post, which I'm only just reading:
So perhaps sudden-onset ME could be the equivalent of the 'anamnestic response' that you refer to in relation to RA?

Basic undergraduate stuff it is, but not so basic that an eminent professor of immunology noted for animal models of arthritis in mice can get her head around it, it seems. Or the expert witness for Genentech commenting on the reason why rituximab works in defence of a patent that we got quashed because he had not idea what he was on about (or they).

It takes people, even 'world authorities' by surprise. Somatic mutation to most people means the 'mistakes' that cause cancer. It is a mutation in the DNA of any cell except a germline ovum or sperm cell. It is passed on to daughter cells but not offspring. The quirk of the immune system is that it is the only system in the body that produces deliberate physiological somatic mutation of genes - antibody genes and T cell receptor genes. That is how the body manages to produce billions of variations on a single protein - as discovered by the father of a schoolfriend, Sir Rodney Porter, who sadly died soon after in a car crash and explained by Michael Neuberger who sadly too has died prematurely.

Nobody used to think of these two sorts of mutation in the same way, but mathematically they have the same basic property of randomness and the fact that the antibody mutations are supposed to be 'on purpose' does not absolve some of them from also being 'mistakes'. Its all fascinating and a bit complicated but for me it made sense of a problem I had tried to understand for twenty years.

 

[Bob]

Ah but somebody thinks they have identified the commensal bacterium in cats that might get passed on the pillowcase to the child. Trouble is I cannot remember its name.

I'm sure I'm being a bit dim here, but I can't work out if you've said that in a sarcastic tone (i.e. you don't take the research seriously) or whether it interests you?

There seems to be plenty of research info regarding "acute infectious arthritis" (which seems to be linked to Lyme symptoms, in some cases), which is thought to stem from e.g. pet bites and tick bites, but I think you were referring to an ordinary/chronic type of RA?

 

[Bob]

It takes people, even 'world authorities' by surprise. Somatic mutation to most people means the 'mistakes' that cause cancer. It is a mutation in the DNA of any cell except a germline ovum or sperm cell. It is passed on to daughter cells but not offspring. The quirk of the immune system is that it is the only system in the body that produces deliberate physiological somatic mutation of genes - antibody genes and T cell receptor genes. That is how the body manages to produce billions of variations on a single protein - as discovered by the father of a schoolfriend, Sir Rodney Porter, who sadly died soon after in a car crash and explained by Michael Neuberger who sadly too has died prematurely.

Nobody used to think of these two sorts of mutation in the same way, but mathematically they have the same basic property of randomness and the fact that the antibody mutations are supposed to be 'on purpose' does not absolve some of them from also being 'mistakes'. Its all fascinating and a bit complicated but for me it made sense of a problem I had tried to understand for twenty years.

I see. Thanks very much for the explanation, Jonathan. I think I'm beginning to get a basic understanding. You are very patient! (I have to say, it's very nice, and unexpected, to have a direct line to an Emeritus Prof!)

If I've understood correctly, then autoimmunity is a somatic mutation too far (or a number of mutations too far) within the immune system, such that certain immune cells can no longer recognise cells that belong to the self.

 

[Jonathan Edwards]

I'm sure I'm being a bit dim here, but I can't work out if you've said that in a sarcastic tone (i.e. not taking the research seriously) or whether it interests you.

There seems to be plenty of research info regarding "acute infectious arthritis" (which seems to be linked to Lyme symptoms, in some cases), which is thought to stem from e.g. pet bites and tick bites, but I think you were referring to an ordinary/chronic type of RA?

I don't have the courage to use sarcasm in the strict sense (I am afraid of upsetting people to their face) but I do sometimes use gentle irony and I am aware this often confuses people because they are not sure whether I am being serious. In this case I am quite serious and I rather like this story, but I get ribbed about that by my colleague who refuses to have anything bad said about cats. It's one of those stories it is hard to know what to make of. At least its a biological explanation. It would be for RA twenty years later.

Ordinary infectious arthritis is straightforward, occurring at the time and with no long term effects if treated in time and no autoimmunity. Lyme produces a post infective syndrome a bit like Reiter's, which is not autoimmune but some form of persistent hypersensitivity I think. It is complicated by the organism also hanging around a long time in a hidden form.

 

[Jonathan Edwards]

If I've understood correctly, then autoimmunity is a somatic mutation too far (or a number of mutations too far) within the immune system, such that certain immune cells can no longer recognise cells that belong to the self.

Yes, or they no longer recognise self proteins AS self. They recognise them as if they were foreign and manufacture large quantities of what are now damaging antibodies.

 

[Bob]

In this case I am quite serious and I rather like this story, but I get ribbed about that by my colleague who refuses to have anything bad said about cats.

Hehe... And we have lots of cat lovers on this forum, so do be careful what you say about them!

 

[heapsreal]

It is indeed all speculation but I have to keep banging on about the fact that talk of infective triggers in autoimmunity is almost always based on empty dogma and it constantly needs countering. Spending another fifty years looking for infections that are irrelevant seems to me to be the wrong way to use our resources! It seems to make sense on a simplistic analysis but nobody ever cracked a disease with a simplistic analysis. Nature is subtle. But she is not vindictive so if you think carefully you can find the right answer.

This seems the total opposite of what they are finding in MS research and this seems more closer related to ME then RA. It doesnt seem like a waste of money when they are getting good responses treating ebv in MS as well as improving the function of T cells with vaccines to ebv.

 

[Leopardtail]

I don't have the courage to use sarcasm in the strict sense (I am afraid of upsetting people to their face) but I do sometimes use gentle irony and I am aware this often confuses people because they are not sure whether I am being serious. In this case I am quite serious and I rather like this story, but I get ribbed about that by my colleague who refuses to have anything bad said about cats. It's one of those stories it is hard to know what to make of. At least its a biological explanation. It would be for RA twenty years later.

Ordinary infectious arthritis is straightforward, occurring at the time and with no long term effects if treated in time and no autoimmunity. Lyme produces a post infective syndrome a bit like Reiter's, which is not autoimmune but some form of persistent hypersensitivity I think. It is complicated by the organism also hanging around a long time in a hidden form.

Had to laugh when I read that, I also get mistaken for sarcastic when being ironic once in a while, but like you hate hurting people's feelings

 

[Marco]

I don't have a position on an environmental influence on autoimmune diseases but this paper just popped up suggesting, based on large scale epidemiology studies, that being HIV positive (and presumably receiving HAART) may reduce the risk of developing MS. Several possible mechanisms are discussed including the possible impact of antiretroviral treatment on HERVs :

HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study

http://jnnp.bmj.com/content/early/2014/07/16/jnnp-2014-307932.full

Conclusion

This report is the largest record linkage study undertaken to investigate a possible association between HIV and MS. Our investigation revealed that having HIV, and presumptively being on HAART, provided a significant and potentially protective effect in relation to the risk of development of MS. The magnitude of this effect (>60%) is at the highest level of any prognostic risk factor investigated to date. Nonetheless, there are inevitable methodological uncertainties in our study design and our findings should be regarded as speculative rather than definitive.

(even with such large samples the confidence intervals still look pretty wide to me).

 

[heapsreal]

Had to laugh when I read that, I also get mistaken for sarcastic when being ironic once in a while, but like you hate hurting people's feelings

I think it's more to do with out being able to answer anything opposing anything to do with B cells. Still waiting for a reply from the experts on how treating ebv in MS has helped and also how T cells which are said to be Unimport in immune/autoimmune diseases. Also how infections have nothing to do with autoimmune illnesses even though research has been quoted several times.

Also still 30 yrs of research that all of the sudden doesn't matter.

Aussies are use to the poms coming second but probably third. Might help if they look into research done by the Americans(klimas/peterson/chia and co) and the Aussies at Griffith university.


I was under the impression that scientists had good lateral thinking but it seems once they are onto a theory it doesn't matter.