Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Firestormm]

Yes, I agree. I doubt the persistent presence of pathogens is important. I think the symptoms are more likely to be caused by the mediators that normally respond to pathogens but in ME they just keep going without, or with no more than the trivial endemic microbes that we all have.

Can you expand on that a bit more, Professor? Especially in respect of the 'mediators' and how they might result in the kind of symptoms we collectively experience perhaps. Thanks.

 

[lansbergen]

Yes, I agree. I doubt the persistent presence of pathogens is important. I think the symptoms are more likely to be caused by the mediators that normally respond to pathogens but in ME they just keep going without, or with no more than the trivial endemic microbes that we all have.

That still leaves the question what started the proces.

 

[froufox]

Yes I'd really like to understand this more too...I get the basic gist of autoimmunity as that is what it sort of feels like a lot of the time (body attacking itself), but I cant get my head around die-off reactions/herxes (eg feeling poisoned, more fatigued etc) that Ive personally experienced with antibiotics, as well as many other pathogen killers that ive tried that don't have any immunomodulatory properties as far as i know (eg olive leaf), followed by very clear improvements (even if not a cure), if we dont have any more active pathogens than a regular person. Thanks for any more thoughts.

 

[froufox]

could it be that since the immune system is dysregulated/unbalanced (eg th1/th2 imbalance), apart from the resultant autoimmunity aspect, it is also left unable to fight off pathogens as a result of this, and so the pathogens do end up gaining more of a foothold so to speak?

 

[Firestormm]

I think it is always worth keeping in mind that we are also individuals with other (perhaps not yet diagnosed or recognised) health issues that may be quite separate from whatever model ME turns out to be; although they could be contributing to our general symptoms and impression of what constitutes ME for each of us.

If a model for ME is tied to autoimmunity, and that is able to be treated with something like, or indeed, Rituximab; it is possible that our health doesn't miraculously improve: and all our symptoms dissipate. This may have nothing to do with the effectiveness of the drug should it be rolled out to clinics across the land.

There has been so much speculated about, so many papers produced, somethings will need to be dropped as workable theories as better science emerges. I don't know. Maybe autoimmunity can account for my current state of health - but it's also possible it can't.

Probably sound like I'm teaching y'all to suck eggs...

 

[Marco]

Yes, I agree. I doubt the persistent presence of pathogens is important. I think the symptoms are more likely to be caused by the mediators that normally respond to pathogens but in ME they just keep going without, or with no more than the trivial endemic microbes that we all have.

Could a simple experiment be set up to test various hypotheses?

(a) Common (new) infections don't elicit an abnormal immune response in ME/CFS patients v controls;

(b) .................................................. elicit an abnormal immune response;

(c) in either of the above cases ME/CFS patients self report a higher level of subjective symptoms than controls.

OK there's a need to rule out various confounding factors but it sounds doable (in fact I seem to remember some recent research on reactions to vaccines I think - can't remember what they found).

 

[froufox]

Hasn't Dan Peterson found about 20-30 times or even more, the number of pathogens in people with ME/CFS as compared to controls. I cant remember the exact details, or if these were active infections or not, but it was posted by a patient of his on this forum a few yrs back. He does do extensive testing for pathogens.

 

[Legendrew]

That still leaves the question what started the process.

By start the process, are you referring to what started the immune set-up prior 2-3 years prior to getting ill, or are you referring to the trigger which then caused people to become symptomatic?

With most autoimmune diseases the set-up occurs a long time before the symptoms - I think this was discussed a few pages back - with the potential to have been set up 2-3 years prior to symptom onset. In ME, the rapid onset is likely a result of any overstimulation of the immune system whether it be from viruses, bacteria, stress or otherwise triggering the pre-developed weakness. As such I think looking at initial triggers is a bit of a blind alley - however it would be interesting to know what triggered the initial set-up going but this would be very difficult to do considering everyone at this stage is likely asymptomatic. For me I had MMR/tetanus vaccines that triggered everything off, but I would be incredibly surprised if any of the attenuated virus remains active within my system today. As I would expect in most patients regardless of the initial trigger.

The trouble I find here is in not extrapolating my personal experiences wrongly onto the whole population - I constantly have to remind myself of the different sub-groups that people may fall into and for this reason I still think pathogen studies are worthwhile - just not from an initial trigger standpoint.

 

[voner]

The remarkable thing about antibodies is that they are proteins which are all more or less identical except for their antigen binding sites, which are carried on the ends of two arms a bit like crab claws. The binding sites can be more or less any shape and so can mimic any other receptor or enzyme or adhesion protein you like, at least in theory. Some autoimmune diseases are easy to explain. In people with antibodies to the basal layer of skin they makes the skin come off in blisters - not too puzzling. In RA things are more subtle because the antibodies are not in fact against joints. They seem to cause the problems they do by forming small complexes that happen to bind a particular receptor. That receptor turns out to be present in joints, pericardium, pleura, lung, eye sclera, subcutaneous tissue, but only at pressure points, bone marrow, lymph node and spleen. And the disease affects those 9 places and nowhere else much. It was finding something that was present at all 9 sites that led us to the B cell story and rituximab.

So the autonomic system could be affected by antibodies to neurotransmitters or receptors or it could be that autonomic nerves can get caught up in some more general antibody interaction. The question would be how all the different features can be tied together with one explanation. The problem might be that this might be oversimplifying if there are several diseases going on. Cytokines or neurotransmitters and receptor might be in the story. And even with one story different symptoms might come from different steps in a chain. The problem for me is less thinking of an explanation and more of trying to narrow things down.

Thanks! that was enlightening. So in RA did the symptoms seem related to the B cell theory and if not, how did you folks root it out?

 

[Bob]

Jonathan Edwards

Hi Jonathan,
I don't know if this research paper might hold any interest for you. (I don't think it's been highlighted in this thread before.)
The results are perhaps not as distinct as they first appear from the abstract, but I thought it might be worthwhile to bring it to your attention nevertheless, for you to assess for yourself.

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation
Michael Maes, Karl Ringel, Marta Kubera, George Anderson, Gerwyn Morris, Piotr Galecki, Michel Geffard
Journal of Affective Disorders - 5 September 2013 (Vol. 150, Issue 2, Pages 223-230)
doi:10.1016/j.jad.2013.03.029
http://www.jad-journal.com/article/S0165-0327(13)00254-1/abstract


There's a helpful very brief analysis by our Simon (Simon) here:
http://forums.phoenixrising.me/inde...al-translocation-in-me-cfs.23198/#post-355369

 

[Marco]

To be honest I find that study difficult to interpret. Monocytes migrate into all tissues pretty much and I think it may be a mistake to call this 'immunity'. I am not clear why they thought the monocytes were causing anxiety if they were already causing the anxiety socially. I fin this sort of mouse study a bit far away from the problem in hand!

Without having access to the full paper, what I took out of this (accepting that I've a tendency to speculate well beyond the published data) is that after induced stress, they took standard measurements of stress related behaviour and were able to correlate severity of these behaviours with the level of monocytes recruited (correlation not equating to causation of course).

But activated brain monocytes do release pro-inflammatory cytokines which are also long associated with anxiety states and I assume they are proposing that its this mechanism of chronic inflammation without tissue damage that leads to long term anxiety states even when the initial stressor is removed.

What I thought might be interesting/novel is that this also provides a model for brain inflammation/sickness behaviour arising without needing any monocyte infiltration of the blood brain barrier as per proposed for rheumatoid arthritis. Probably not relevant though.

 

[Jonathan Edwards]

I think we may be going back over the same ground with the mediators and triggers (environmental or stochastic for me).

Yes I'd really like to understand this more too...I get the basic gist of autoimmunity as that is what it sort of feels like a lot of the time (body attacking itself), but I cant get my head around die-off reactions/herxes (eg feeling poisoned, more fatigued etc) that Ive personally experienced with antibiotics, as well as many other pathogen killers that ive tried that don't have any immunomodulatory properties as far as i know (eg olive leaf), followed by very clear improvements (even if not a cure), if we dont have any more active pathogens than a regular person. Thanks for any more thoughts.

I wonder if antibiotics are producing an exacerbation through their various other effects on normal body physiology. Most of them poison bacteria more than us but they still poison us a bit. We may all have low level immunity to them as well. If ME is a situation where 'alarm responses' from the innate immune system are triggered too easily because an autoantibody interferes with their balance/control then maybe this would work.

 

[Jonathan Edwards]

Thanks! that was enlightening. So in RA did the symptoms seem related to the B cell theory and if not, how did you folks root it out?

We spent ten years looking at joint tissue. The logic was that RA affected joints but nobody knew why. That did not seem too surprising because almost nobody had studied joint tissues with modern techniques. We gradually listed all the unusual features of joint cells. Then one day we realised that the most striking features of joint lining cells were the same as the cells in bone marrow and lymph node that 'nurse' B cells. The story got long and complicated but one strange thing is it looks as if bone marrow, which evolved later than joint lining, borrowed these features from joint lining cells and put them to new uses. Anyway, it made us think that joint lining must be susceptible because it looks a bit like bone marrow. We then realised that that would implicate antibody receptors and remembered that nearly ten years earlier we had found antibody receptors were n strange places in joint lining. We went back and had another look and the same receptor turned up in all the other tissues involved. It was a rather circuitous route but in the end it all fitted together - with fifty one steps and four loops (if I remember rightly). Which, I suspect is why it is not surprising people find it hard to get their head round the whole thing!

 

[Legendrew]

I wonder if antibiotics are producing an exacerbation through their various other effects on normal body physiology. Most of them poison bacteria more than us but they still poison us a bit. We may all have low level immunity to them as well. If ME is a situation where 'alarm responses' from the innate immune system are triggered too easily because an autoantibody interferes with their balance/control then maybe this would work.

From there it follows that treating the viruses/bacteria that everyone has at a low level does indeed help the symptoms but the over-reaction still remains so once you come off the drug and the low levels of pathogens that everyone harbors return and once again crosses the lowered threshold, the symptoms return.

I'm sorry since I brought this topic back up but it's good to get those things straight in your mind since pathogens are a big talking point in ME for many people.

 

[Jonathan Edwards]

Jonathan Edwards

Hi Jonathan,
I don't know if this research paper might hold any interest for you. (I don't think it's been highlighted in this thread before.) The results are perhaps not as distinct as they first appear from the abstract, but I thought it might be worthwhile to bring it to your attention nevertheless, for you to assess for yourself.

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation
Michael Maes, Karl Ringel, Marta Kubera, George Anderson, Gerwyn Morris, Piotr Galecki, Michel Geffard

Yes, I have seen this. The problem for me here is that antibodies to molecules as small as 5HT are not really antibodies in a functional sense. The reason for this is that antibodies only start signalling they have bound to something if at least two antibodies can bind to it or it is stuck to something else. Antibodies to 5HT should be 'silent' as far as I can make out, so I find it hard to see where the story would lead.

 

[bertiedog]

Talking about bacteria and infections I find that for over 30 years and especially since crashing in 2000 I can go down very quickly with a throat infection that gives me identical symptoms every time. Nothing changes except maybe the extent of the burning I get in my throat.

One of the main symptoms that alerts me to the fact I am going to need antibiotics is that I get horrible strong muscle pains which shoot around my body. Normally I don’t have a lot of muscle pain only a bit at the end of a walk and nothing like what I experience when I need the antibiotics. As well as these very strong shooting muscle pains I also start feeling very unwell and have severe lack of energy and just have to lie around and do nothing feeling very depressed. I might also experience dizzy spells and have a need to sleep a few times in the day which I don’t normally have to do.

What surprises me is how quickly the infection starts and how quickly I can feel so very ill and also I don’t understand how the symptoms are identical every time. Once about 30 years ago my then GP swabbed my throat but I was told nothing grew and I didn’t need antibiotics yet I never get better unless I have them, my immune system just cannot fight this. However once I get started on the antibiotics I start to feel human again within 48 hours although of course it’s a few more days before I could say I feel really much better.

Does this type of problem/response relate in any way to an autoimmune problem I wonder? I don't understand how it would fit the theory.

Pam

 

[voner]

We spent ten years looking at joint tissue. ..............We gradually listed all the unusual features of joint cells. Then one day we realised that the most striking features of joint lining cells were the same as the cells in bone marrow and lymph node that 'nurse' B cells. The story got long and complicated but one strange thing is it looks as if bone marrow, which evolved later than joint lining, borrowed these features from joint lining cells and put them to new uses. Anyway, it made us think that joint lining must be susceptible because it looks a bit like bone marrow. We then realised that that would implicate antibody receptors and remembered that nearly ten years earlier we had found antibody receptors were n strange places in joint lining. We went back and had another look and the same receptor turned up in all the other tissues involved......

how interesting... in ME you have the Rituximab data....also... so you might be looking at a bone marrow link also? You want to do any speculation yet?

 

[Sasha]

There are all sorts of immunomodulatory drugs that people have tried over the years (including, famously, Ampligen) and antivirals (Valcyte, Vistide, etc.) and some people do seem to have a good response though, due to lack of funding, there are very few trials. Even with the antivirals I've seen suggestions that these work by their immunomodulatory properties rather than their direct antiviral action (I've seen this said about Valcyte for HHV-6).

If ME (at least for some people, and in roughly the proportion found by Fluge & Mella) is a B-cell, autoimmune issue, is it likely that these drugs are indirectly addressing that issue even when they've been assumed to be acting on other elements of the immune system or on particular viruses?

 

[froufox]

Thanks for replying. This leaves me wondering why there would be improvements in the ME symptoms afterwards, in both energy and cognitive function, if the antibiotics themselves were only acting as a poison. Perhaps Ive not quite understood tho. I know the immune system is extremely complex.

A herx is quite a common experience in lyme, its an endotoxin reaction when bacteria are killed off and the person feels temporarily worse before feeling better. It does describe what I go through quite well, i think.

I think we may be going back over the same ground with the mediators and triggers (environmental or stochastic for me).


I wonder if antibiotics are producing an exacerbation through their various other effects on normal body physiology. Most of them poison bacteria more than us but they still poison us a bit. We may all have low level immunity to them as well. If ME is a situation where 'alarm responses' from the innate immune system are triggered too easily because an autoantibody interferes with their balance/control then maybe this would work.

 

[heapsreal]

A possible good biomarker in ME is low nk function, this also occurs in some other auto immune illnesses. Griffith uni in australia have found that its low bright cell nk function that is low in ME patients. I did hear a rumor that they were going to do a study with other auto immune illnesses with low nk function, MS and RA from memory and compare nk function as well as bright and dim cell nk function so they can possibly nail down a diagnostic biomarker for ME.

If one looks at the job of nk cells, i think it would be quite common to have issues with ongoing viral infections as its the job of nk cells to control these infections. Horse or the cart scenario too if its the infections keeping us ill or some type of auto immune issue or combination??