Do MEs cause CFS?

[Jonathan Edwards]

The way I was thinking about ME/cfs,although all this maybe incorrect and not even remotely correct but here goes.If B cells fill up with EBV and T cells keep them in control the cytokines are like the whipping master getting the T cells to work and everything is working,its just you have high levels of cytokine signalling.If you wallop those b cells with rituximab then the t cells wont need as much signalling(cytokines) to keep things under control so you will feel better.

That is a very reasonable suggestion but the time course of rituximab is too slow for it to be right. B cells are removed within hours. T cells might take a week to calm down and reduce cytokine levels. But response to rituximab can take 9 months to evolve - consistent with the time it takes for the autoantibodies to decline.

 

[Jonathan Edwards]

... some PWME appear to pick up multiple bugs while others report apparently no or few colds/flus etc over a period of many years. One way I've rationalised this is that the immune system may already be activated and producing the symptoms of 'sickness behaviour' so any new infection may be present (and dealt with) but goes unnoticed.

BUT. It just occurred to me that I experience something else which would contradict this theory. Over he same period of time I appear to have developed an enhanced reaction to insect bites.

Mossies (obviously) can carry viruses and presumably also bacterial infections so you would expect the same immune pathways to be triggered by colds/flus and bites although I believe that mossie bites (and perhaps those of other bloodsuckers) alter the victim's immune response to aid feeding. Perhaps also (and here I admit my ignorance) insect bites might trigger some allergy type immune pathway?

Whatever, I find a very distinct qualitative difference between my response to the two immune challenges. I've no idea if this is common in PWME and can't say what; if anything, it means?

I agree that it is not clear what is going on here. However, as MeSci says, there are several parallel pathways to think of. Intracellular organisms can recruit completely different arms of the immune response from extracellular ones. As I will discuss in the SMRC thread I think we need to get away from a single explanation of sickness behaviour. There is quite a bit of YinYanging going on and we may need to separate the Yins from the Yangs. We also need to pay attention to different sites, where responses may be modulated differently.

 

[Marco]

I agree that it is not clear what is going on here. However, as MeSci says, there are several parallel pathways to think of. Intracellular organisms can recruit completely different arms of the immune response from extracellular ones. As I will discuss in the SMRC thread I think we need to get away from a single explanation of sickness behaviour. There is quite a bit of YinYanging going on and we may need to separate the Yins from the Yangs. We also need to pay attention to different sites, where responses may be modulated differently.

Many thanks

Just catching up on the SMRC thread now.

 

[MeSci]

Many thanks

Just catching up on the SMRC thread now.

I can't find an SMRC thread - do people mean this thread?

I've got an awful lot of catching up to do, having just seen that one!

 

[Bob]

I can't find an SMRC thread - do people mean this thread?

I've got an awful lot of catching up to do, having just seen that one!

Yes, that's where Prof Edwards is reporting on his conference experience.

 

[WillowJ]

There are three types of muscle willow: skeletal, smooth, & cardiac
Because the heart must beat continuously, it requires a muscle type with massive stamina

Thanks. I knew this stuff once but my memory degrades, and I wear out when I try to look it up as a refresher.

I have been looking into the same issue. I have managed to work out how fever is implemented, but not the full triggering chain nor exactly how the body 'decides' its fever time (meaning the biochemistry, not the functional pattern). It would be interesting to compare notes once I can give it some attention again.

Comparing notes would be cool, if I can at some point focus enough to look at things in detail again (it's been some time since I was trying to figure this out).

 

[WillowJ]

It may not be a primary problem but autonomic/vascular issues that result in reduced blood flow/ischemia in the muscles, brain or both could produce the necessary 'danger signals' required to activate already primed glia in a scenario similar to ME5.
...

One other mechanism that I'd considered is heat shock proteins. Jammes and others have found attenuated HSP production following exercise in ME/CFS patients. As I understand it HSP production normally peaks at around 48 hrs post exercise (which suggests to me, if they are doing their job properly, that this should coincide with the maximal cellular/oxydative stress). If this repair mechanisms is defective in ME/CFS patients then 48 hrs post exercise might be when you might expect symptoms to peak. Highly speculative but this timescale does fit that described in the International Consensus Primer :

“prolonged recovery period: usually 24 hours, often 48 but can last days, weeks or cause a relapse”

Worth bearing in mind though that PEM can also often follow purely mental exertion which would make the HSP mechanism less likely.

Just some thoughts.

I always thought there were multiple mechanisms in play. Dysautonomia, channelopathy, brain inflammation, and/or mitochondrial dysfuction could account for symptoms occurring during and immediately post-exercise in some patients.

HSP, autoimmune reactions involving any of the other components, and anything else that takes time to build up, could contribute to delayed reactions. Metabolic acidosis might fit here, which would be typically missed as we will postpone an appointment when in the middle of a bad crash.

 

[WillowJ]

Yes, it does, but maybe in more than one way. The question is why the immune system fails to switch off for those with ME. My thought is that the immune system gets 'reset' to an inappropriate overresponsiveness. My guess is that the most likely reason for re-setting is the generation of an autoantibody that feeds back on the system in a way it should not. So this for me is likely to come under what I call ME5. However, there is a question about whether the virus that produces the first symptoms is the chicken or the egg. If the immune system was already reset that might be the cause of initial severe symptoms. I also think that some viruses may have a particular ability to reset the immune system maybe without autoimmunity. EBV obviously comes to mind and coxsackie viruses also have a reputation for doing odd things. In these cases the reason for progressing to ME might perhaps be genetic. In other words I think the answer is yes but it may be several different types of yes.

Rituximab would be appropriate if resetting of the immune system was driven by autoantibody - which for me would be ME5 and also ME1 and ME4 but not ME2. (Viruses could fit in with ME1 and ME4 as well.) Otherwise I am not sure it is relevant, except that it might also be relevant to an EBV+genetic mechanism since it can clear EBV, which is unusual in living in B cells.

That's my current guess, and it's only a guess.

If the immune system was already reset or if it is primarily genetic, what would cause it to not happen until one was 16 or 30 or whatever? Why then and not some other time? I am curious how it might work. Do you know how it works in RA and traditional autoimmune disease, too?

 

[Snow Leopard]

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.

This is what I was wondering about though. Who has actually systematically examined the data from various longitudinal studies?

I mean it is obvious that it is not a simple cause and effect - eg an infection is neither necessary nor sufficient for an autoimmune disease to develop, but infections necessarily alter immune states and may increase the risk, hence why I am asking whether you or anyone else knows of serious attempts to measure this risk (or lack thereof).

Otherwise, assumptions either way could easily be wrong.

I also have another question, which you might be more interested in, but I'm still working out how to phrase it...

 

[Jonathan Edwards]

If the immune system was already reset or if it is primarily genetic, what would cause it to not happen until one was 16 or 30 or whatever? Why then and not some other time? I am curious how it might work. Do you know how it works in RA and traditional autoimmune disease, too?

The immune system is a constant 'random number generator' or at least random protein sequence generator when it comes to T cell receptors and antibodies. Most of the T cell generating is over by late teens but new antibodies are made every day until you die. The idea we came up with in RA, and extended to other autoantibody-related disease, and as a result successfully introduced rituximab treatment, was that the resetting occurs when an antibody is generated by chance that can feedback on its own B cell to stimulate further production through a rogue loop. In fact you need more than one B cell clone and more than one antibody, to feed off each other, but that is getting complicated. This would explain why almost all autoimmune diseases appear in genetically susceptible people at random in time rather than in relation to any environmental stimulus.

 

[Jonathan Edwards]

This is what I was wondering about though. Who has actually systematically examined the data from various longitudinal studies?

I mean it is obvious that it is not a simple cause and effect - eg an infection is neither necessary nor sufficient for an autoimmune disease to develop, but infections necessarily alter immune states and may increase the risk, hence why I am asking whether you or anyone else knows of serious attempts to measure this risk (or lack thereof).

Otherwise, assumptions either way could easily be wrong.

I also have another question, which you might be more interested in, but I'm still working out how to phrase it...

You don't have to do any systematic examining. Just look at the standard graphs in the textbooks. They are done on enough numbers to have very little noise. You cannot ascertain the risk for individual infectious agents because of too many confounders but there are no known infections or even classes of infections that would give an epidemiology remotely like the incidence curves. Moreover, there is no cogent hypothesis that links infection to autoimmunity. The old molecular mimicry idea doesn't actually make sense. It only works if you add in an extra magic ingredient X. And you do just as well just with the magic ingredient and no mimicry. The only magic ingredient needed is immunoglobulin gene reaarangement that occurs every time an antibody is produced.

 

[daisybell]

The immune system is a constant 'random number generator' or at least random protein sequence generator when it comes to T cell receptors and antibodies. Most of the T cell generating is over by late teens but new antibodies are made every day until you die. The idea we came up with in RA, and extended to other autoantibody-related disease, and as a result successfully introduced rituximab treatment, was that the resetting occurs when an antibody is generated by chance that can feedback on its own B cell to stimulate further production through a rogue loop. In fact you need more than one B cell clone and more than one antibody, to feed off each other, but that is getting complicated. This would explain why almost all autoimmune diseases appear in genetically susceptible people at random in time rather than in relation to any environmental stimulus.

Does this explanation cover why those of us who seem genetically susceptible get more than one autoimmune disease? Just wondering aloud here......

 

[Jonathan Edwards]

Does this explanation cover why those of us who seem genetically susceptible get more than one autoimmune disease? Just wondering aloud here......

Some gene variants predispose people to a range of autoimmune mistakes and some only seem to predispose to one particular mistake. For the variants that predispose generally this explanation covers why such people get different autoimmune mistakes randomly at different time.

The exception to the rule is lupus, which is a sort of family of mistakes within one mistake. There seems to be a loop that sets going a whole lot of other loops, like the inside of Swiss watch. In this case all the mistakes may appear pretty much at the same time.

 

[knackers323]

Right, mine is not covered. Does not matter, I know what to do and you might get to it in due time.

Hi @lansbergen can you tell me what you mean by this? Thanks

 

[cornwall13]

Professor Edwards

IN relation to your comment in post 370 above
""This would explain why almost all autoimmune diseases appear in genetically susceptible people at random in time rather than in relation to any environmental stimulus."

Myself, like a lot of people say that their ME started after a particular infection or virus. I can definitely pinpoint when my body changed after a certain virus. Are you saying that basicly ME could of happened at anytime after any Virus, and it just so happens it was after that virus and I just got unlucky? Almost it was just bad luck and if ME didn't develop after that virus it may have after another?

As a lot of people may say that if I didn't catch that virus at that time I would of never in my life developed ME? Or are the genetics of people who develop ME just more prone to getting ME?

 

[Jonathan Edwards]

Professor Edwards

IN relation to your comment in post 370 above
""This would explain why almost all autoimmune diseases appear in genetically susceptible people at random in time rather than in relation to any environmental stimulus."

Myself, like a lot of people say that their ME started after a particular infection or virus. I can definitely pinpoint when my body changed after a certain virus. Are you saying that basicly ME could of happened at anytime after any Virus, and it just so happens it was after that virus and I just got unlucky? Almost it was just bad luck and if ME didn't develop after that virus it may have after another?

As a lot of people may say that if I didn't catch that virus at that time I would of never in my life developed ME? Or are the genetics of people who develop ME just more prone to getting ME?

I think I am saying that for some types of ME this may apply. But it may not apply to others. I suspect nothing is hard and fast here. In conditions like RA for some people there is a very strong genetic risk to get the disease. In others the genetic risk may be slight but the immune mistake can still kick in, but less often.

 

[eve789]

Hi @Jonathan Edwards. Forgive me if this has been addressed elsewhere but there is a sizable proportion of the community that has witnessed Lazarus-like improvements by practicing "extreme mold avoidance." I have been a good responder to antivirals, but experienced an almost complete remission of symptoms after a sejour in the desert (upon returning home I could not enter most buildings in my town). My baseline was 95% bedbound.

I wonder how this might fit into your hypothesized MEs? I am very cautious not to confuse the treatment with the cause. Note: this is something much more than getting toxic from living in a sick building and the sensitivity is extreme, almost paranormal. If I leave a cardboard box out in the rain for a day it can make me feel deathly ill within seconds of getting too close to it (where deathly ill == severe neurological symptoms).

Also if an ANA of 1:10 tells you not much what about 1:40?

Laslty, what about pregnancy? Why are there so many reports of people developing this after pregnancy or feeling better or worse during pregnancy (as is true in other autoimmune diseases).

Your participation on this forum is pretty much the most awesome thing ever.

 

[Jonathan Edwards]

Hi @Jonathan Edwards. ... a sizable proportion of the community that has witnessed Lazarus-like improvements by practicing "extreme mold avoidance." I have been a good responder to antivirals, but experienced an almost complete remission of symptoms after a sejour in the desert (upon returning home I could not enter most buildings in my town). My baseline was 95% bedbound.

I wonder how this might fit into your hypothesized MEs? Note: this is something much more than getting toxic from living in a sick building and the sensitivity is extreme, almost paranormal. If I leave a cardboard box out in the rain for a day it can make me feel deathly ill within seconds of getting too close to it (where deathly ill == severe neurological symptoms).

Also if an ANA of 1:10 tells you not much what about 1:40?

Laslty, what about pregnancy? Why are there so many reports of people developing this after pregnancy or feeling better or worse during pregnancy (as is true in other autoimmune diseases).

I think the sensitivity to mould would come under my ME3, along with sensitivity to other sensory stimuli like light and sound. I do not think what you describe could be explained in terms of an immunological or allergic reaction. The only explanation that I can think of is that the sensitivity is within the brain sensory pathways, perhaps in the basal ganglia. Sense of smell can have very powerful effects on us, even in the normal situation. That could fit with the popular theory of microglial changes perhaps.

An ANA of 1:40 might be significant but it is always difficult to know because a small proportion of healthy people have ANA at that level.

And I would be cautious about interpreting associations with things like pregnancy because people will always remark on associations with life events even if they do not occur more often than chance.

 

[knackers323]

Hi @Jonathan Edwards I have had a ANA speckled pattern titre of 640:1. What do you believe this indicates?

Thanks for your time on PR

 

[Jonathan Edwards]

Hi @Jonathan Edwards I have had a ANA speckled pattern titre of 640:1. What do you believe this indicates?

Thanks for your time on PR

I am very tempted to think that where people have speckled ANA at that sort of level and fatigue that the antinuclear antibodies are involved in the cause of the fatigue - what I called ME1. The situation may be clearer if a specific antigen screen has been done to see what the speckled pattern is due to - anti-Sm, anti-RNP, anti-Ro etc etc. Labs tend to call this an ENA screen although ENA is not an ideal term for these antigens. If the speckling is due to anti-Ro then it would be fairly clear that this was a Sjögren's type fatigue.

The same might apply at 1:40 but it is just that there is no clear limit to the 'normal range' for the test so it becomes a matter of probability.