Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[Jonathan Edwards]

Surely there is no doubt that the Th1 response is responsible for activating cell mediated immunity. And if we are presuming ME/CFS might be driven by intracellular pathogens like non-cytolytic enteroviruses (defective enteroviruses), then the activation of the Th1 mode, or lack thereof, should be an area of exploration in ME/CFS.

This is all a myth as far as I can see. The great majority of my immunology colleagues go around talking about TH1/TH2 balance but there are a few of us that just sit in the corner and shake our heads. TH1 cells play an important role in antibody production. With intracellular pathogens we are mostly talking about CD4 cells interacting with CD8 cells, although antibody is also relevant. (We now know that the TRIM21 system imports antibody into cells to kill viruses.) I am not sure whether it matters if they are TH1 or TH2 cytokine producers.

For me Th1 and Th2 cells are a bit like the cooks in a big kitchen that either prepare vegetables (Th1) or meat (Th2). There is no such thing as a 'vegetarian response' or a 'meat-eater's response'. Each customer may be dealt with by a vegetarian starter, a meat main course and a sorbet for afters or any other of all sorts of combinations. The immune response is of that order of complexity - in fact more so. Most of the time it is meat and two veg.

Really I agree with Eeyore that TH1/TH2 is a much less useful distinction than the old fashioned cell mediated and antibody-mediated immunities - and even then there is never one or the other - always a bit of both intertwined. And now that we know that one form of antibody effector mechanism - small immune complexes (large ones work through complement) - uses a 'TH1' cytokine - TNFa.

So when people talk of finding increases in Th1 cytokines they are confusing themselves because most of the TNFa comes from macrophages - not T cells at all. Most of it isn't really a T anything. Almost everyone working in immunology tries to squeeze their results into this TH1/TH2 balance idea but there simply isn't any basis for it. People use the buzzwords because it gets them grants and gets their papers in trendy journals but it is not science as far as I can see. Rheumatoid arthritis was for a long time firmly established as a TH1 disease. But then TH17 cells came along so it became trendy to call it a TH17 disease - until we found that anti-IL17 was no good but worked fine for psoriasis. And then it became clear that it was an antibody mediated disease after all.

As far as I know there is no evidence whatever for a 'balance' between TH1 and TH2. More TH1 does not imply less TH2, just as more vegetables does not imply less meat. You might want lots of both. The systems dynamics of the immune system are much more complex and like a high class kitchen. Broderick is on to this sort of thing with his mathematical models but I am not clear that he has enough data to validate them.

Th1/Th2 shifting is immunobabble I am afraid.

 

[nandixon]

You might want lots of both.

That's certainly a suggested possibility from the two Hornig, et al., papers, in which most of the cytokines across the board - in both plasma (for the long term patients) and in cerebrospinal fluid - were found to be low in ME/CFS.

 

[Eeyore]

@Jonathan Edwards - I will try to stick with humoral/cellular immunity as usually that's what I mean when speaking of Th1/Th2, and it's more accurate probably to describe it as such. Yes, the 2 are intricately intertwined and you almost always have some of each - although not completely true (e.g. we don't know of any antibody in the seronegative SpA's).

You are something of an expert in RA and Rituximab, which is quite useful right now in understanding ME I believe (as I do believe the Fluge/Melle trial will show efficacy and entirely redirect ME research going forward). They may not be able to identify why it works - but just the fact that it does opens up so many questions and firmly establishes an organic basis for disease.

One question that has come up in my mind is that I have read of a number of cases where AS responds to rituximab - and this doesn't seem to make sense, because the autoinflammatory diseases seem to be mediated through IL-17, IL-23, TNFa, etc. No antibodies are involved (I don't think this is an oversight either - I believe we would have found them by now). I'm curious what the mechanism might be for rtiuximab working in AS (although I know it is not first line by any means and works far less often than it does in RA).

Another aspect of ME that cannot be ignored is female preponderance. It's rather odd sometimes being a man with ME. As a rheum, you're pretty experienced with a broad array of autoimmune disease. In general, I would say that the antibody mediated diseases show female preponderance (i.e. autoimmune) vs the autoinflammatory diseases which show male preponderance (especially AS). I suppose this would support a role for an antibody - but if we look deeper at why women are more susceptible to antibody mediated autoimmunity (microchimerism? what is the current best theory in your opinion?), does this offer any insights into ME pathogenesis beyond suggesting the possibility of antibody involvement? Is there some difference in B-cell regulation or function in men and women?

 

[Jonathan Edwards]

@Jonathan Edwards

One question that has come up in my mind is that I have read of a number of cases where AS responds to rituximab - and this doesn't seem to make sense, because the autoinflammatory diseases seem to be mediated through IL-17, IL-23, TNFa, etc. No antibodies are involved (I don't think this is an oversight either - I believe we would have found them by now). I'm curious what the mechanism might be for rtiuximab working in AS (although I know it is not first line by any means and works far less often than it does in RA).

When I left rheumatology in 2010 my understanding was that there was no good evidence for rituximab working in AS and that a trial had been negative. There will always be placebo responses I guess in a few case reports. It is just conceivable that B cells have some ancillary role in AS but like you I think it very unlikely. Everything points to a CD4/CD8 co-operation or maybe even NK cell involvement through Class I receptors (NKIR/NKAR).

Another aspect of ME that cannot be ignored is female preponderance. In general, I would say that the antibody mediated diseases show female preponderance (i.e. autoimmune) vs the autoinflammatory diseases which show male preponderance (especially AS). I suppose this would support a role for an antibody - but if we look deeper at why women are more susceptible to antibody mediated autoimmunity (microchimerism? what is the current best theory in your opinion?), does this offer any insights into ME pathogenesis beyond suggesting the possibility of antibody involvement? Is there some difference in B-cell regulation or function in men and women?

Historical studies in small mammals indicate that females produce a more extensive antibody response to standard challenges. There is a mass of information about the effects of oestrogens on antibody responses too. I have never been sure quite how these play out in the context of normal female humans. However, there is the heuristic argument that antibodies are much more important to females than males because newborn infants have to survive largely on maternal antibody before they have built their own adaptive responses. It is also interesting that most autoantibody mediated diseases are three times as common in women but lupus is nine times as common, as if the same risk works twice (3 squared).

The incidence curves for ME look a bit like MS, rather than RA. That is OK because I personally think MS is an antibody mediated disease too - it will take another ten years before the neurologists see this though. I have a simple mathematical model for the incidence curve for RA based on genes and stochastic B cell receptor generation. MS declines after forty suggesting that it is an error that becomes less likely after a certain time; so does ME. There are ways to build systems dynamics for that but they are very speculative. The other thing about ME is the second incidence peak in adolescence, which starts with no female bias. I have a sort of feeling that there is a neurological factor, like microglial maturation, contributing to this. But it is hard to be sure - very hard.

 

[Eeyore]

@Jonathan Edwards - That's very interesting that there is a bimodal peak age of onset, and that the first peak in late adolescence does not show female preponderance - possibly suggesting 2 different mechanisms leading to a final common pathway. It's particularly interesting to me because I got sick at age 18 and am male. Is there any difference in clinical course or any measurable characteristics, genetics, etc. between the people in each group?

I'm not surprised that we look like MS - whether or not in fact the diseases are antibody mediated. I'm rather agnostic on that point for now - not enough evidence either way, and while the rituximab could be seen as supportive of that theory, it's far from conclusive, and there are alternate explanations.

 

[Jonathan Edwards]

@Jonathan Edwards - That's very interesting that there is a bimodal peak age of onset, and that the first peak in late adolescence does not show female preponderance - possibly suggesting 2 different mechanisms leading to a final common pathway. It's particularly interesting to me because I got sick at age 18 and am male. Is there any difference in clinical course or any measurable characteristics, genetics, etc. between the people in each group?

I'm not surprised that we look like MS - whether or not in fact the diseases are antibody mediated. I'm rather agnostic on that point for now - not enough evidence either way, and while the rituximab could be seen as supportive of that theory, it's far from conclusive, and there are alternate explanations.

Early onset ME is supposed to have a better chance of remission - much better. Otherwise I am not sure that differences have been found.

 

[Marco]

The incidence curves for ME look a bit like MS, rather than RA. That is OK because I personally think MS is an antibody mediated disease too - it will take another ten years before the neurologists see this though. I have a simple mathematical model for the incidence curve for RA based on genes and stochastic B cell receptor generation. MS declines after forty suggesting that it is an error that becomes less likely after a certain time; so does ME. There are ways to build systems dynamics for that but they are very speculative. The other thing about ME is the second incidence peak in adolescence, which starts with no female bias. I have a sort of feeling that there is a neurological factor, like microglial maturation, contributing to this. But it is hard to be sure - very hard.

Very interesting as usual Jonathan. I'm afraid I don't have the time to check the thread at the moment but in pondering this I'm wondering about the relative magnitude of the two ME/CFS peaks. Is it a greater number of males susceptible at the earlier age or a greater number of females later?

 

[Jonathan Edwards]

Very interesting as usual Jonathan. I'm afraid I don't have the time to check the thread at the moment but in pondering this I'm wondering about the relative magnitude of the two ME/CFS peaks. Is it a greater number of males susceptible at the earlier age or a greater number of females later?

My memory is that at 12 the incidence is equal. Then up to about 18 the peak builds in girls but it fails to take off in boys. In adults the second male peak is a flatter version of the female peak at about a third the level throughout. We have had the Norwegian graph on screen in previous threads but I am not sure which ones.

 

[Eeyore]

Interesting, as around 12 is when menstruation / puberty are beginning. I wonder if there is a connection to sex hormones - you mentioned earlier that that may play some role in the predominance of some autoimmune diseases in women.

 

[Scarecrow]

We have had the Norwegian graph on screen in previous threads but I am not sure which ones.

In case anyone's wondering about the Norwegian graph, here's a link

 

[Marco]

My memory is that at 12 the incidence is equal. Then up to about 18 the peak builds in girls but it fails to take off in boys. In adults the second male peak is a flatter version of the female peak at about a third the level throughout. We have had the Norwegian graph on screen in previous threads but I am not sure which ones.

Thanks Jonathan. I found time.

Here's figure 1 again :

http://www.biomedcentral.com/1741-7015/12/167/figure/F1

Shapewise they follow a similar trace but the late incidence in males is lower than the early peak. I would suggest a protective role for androgens but that would imply a greater male incidence in later years. With the caveat that males in their mid 30's may not have the time/incentive to report symptoms (sexist; I know!). Interesting that the rates converge again in later years.

Interesting also that my onset was at what should have been a trough for male onset but I was concerned at the time about sex hormones.

 

[msf]

Does anyone else find it odd that the graph tails off so precipitously? I imagine the average life expectancy in Norway is pretty high, why are there so few cases in over the age of 65? Surely doctors don't start writing off their patient's problems as 'old age' once they reach 65? And is the gradual re-coalescence (or whatever the correct term is) of men and women also likely to be due to sex hormones? I know menopausal women start to get more testosterone just as men are starting to lose some of theirs, but do other hormones reverse in this way?

 

[msf]

Converge! That was the word! Can you teach me English please, Marco?

 

[SOC]

Does anyone else find it odd that the graph tails off so precipitously? I imagine the average life expectancy in Norway is pretty high, why are there so few cases in over the age of 65? Surely doctors don't start writing off their patient's problems as 'old age' once they reach 65?

Oh yeah, they certainly do. My (young) GP was writing off my extreme symptoms as "getting older" when I was less than 50yo.

 

[Scarecrow]

Oh yeah, they certainly do. My (young) GP was writing off my extreme symptoms as "getting older" when I was less than 50yo.

Oh, that's nothing. When I was only 21, my much older GP attributed my extreme stiffness to advancing years.

"Your getting older, you know"

It was not intended to be ironic in any way. Thanks, doc. Helpful.

 

[Jonathan Edwards]

Interesting, as around 12 is when menstruation / puberty are beginning. I wonder if there is a connection to sex hormones - you mentioned earlier that that may play some role in the predominance of some autoimmune diseases in women.

That seems likely but why are there so few other diseases that look like this? I have this feeling that maybe the age-related risk somehow relates to rate of transition or change. I go back to the idea I had about ME having something to do with mismatch. Are these times when certain hormones are going up and others down or something? A peak suggests some sort of trade off between youth related and age related factors. Two peaks is almost like the maxima in a higher order differentiation curve - or more crudely accelerations rather than speeds. I cannot make real sense of it. Maybe the brain changes dramatically at 12 - certainly the ability to introspect does.

An easier way is to say its two different diseases, as you said. We need some more clues. They are probably out there but under a streetlamp with the bulb blown.

 

[leokitten]

My memory is that at 12 the incidence is equal. Then up to about 18 the peak builds in girls but it fails to take off in boys. In adults the second male peak is a flatter version of the female peak at about a third the level throughout. We have had the Norwegian graph on screen in previous threads but I am not sure which ones.

From the Norwegian graph at 12 the difference between boys and girls starts to explode very quickly (so right at the start of puberty) and it doesn't ever come back until 60+ year old.

 

[leokitten]

Also @Hip, @Eeyore, @halcyon, @Jonathan Edwards may I ask why doesn't the pretty glaring fact that ME/CFS is 3:1 female male ratio tell us without doubt that ME is at its root not an infectious disease? Or are the pathogens typically implicated in ME known to have such a strong female bias when it comes to chronic infection?

 

[Eeyore]

@leokitten - Never say never, but yes, I do think it argues against infectious etiology. Most infectious diseases that have a strong predominance in one gender are either sexually transmitted or related to differences in sexual anatomy. That isn't applicable in ME. It's always possible that a certain hormone or variation in anatomy or physiology makes women more susceptible than men, but the exact mechanism for that seems elusive to me.

As is well known to anyone who has read my posts, I do not believe that ME is an infectious illness. I do not believe seronegative Lyme is infectious either. I think this whole family of diseases is post-infectious or post-other trigger.

 

[halcyon]

Also @Hip, @Eeyore, @halcyon, @Jonathan Edwards may I ask why doesn't the pretty glaring fact that ME/CFS is 3:1 female male ratio tell us without doubt that ME is at its root not an infectious disease? Or are the pathogens typically implicated in ME known to have such a strong female bias when it comes to chronic infection?

The ratio in a number of the ME epidemics was 1:1.