Science at the UK CMRC Conference, 1-2 Sept 2014

[A.B.]

So the answer to the historians' eternal question of what causes a war is that human society is so complex that it is inherently unstable from within. A particular set of circumstances within society itself can set off an unstoppable cascade of destruction. I see the immune system as very similar. It is a society of individual cells co-operating but also competing. It is complicated enough to be susceptible to the same internal instabilities.

The ability to evolve implies the possibility of regression. Some B cells are going to be defective. Why are they not being discarded as they should be?

 

[Dx Revision Watch]

Sorry this is O-T (as are the above posts and sorry if there is a later post telling us to stop - I haven't seen it yet and am in a rush as usual) but this weird site lists alternative/earlier terms for psychosomatic.

Yes, the thread had already been taken off topic.

But I considered it was important to note that DSM-5 has dismantled the DSM-IV Somatform Disorders categories and replaced them with a single disorder constuct, Somatic Symptom Disorder, with new criteria.

The site you have referenced is a site maintained by Dr Jon Stone, Consultant Neurologist, Edinburgh.

 

[user9876]

The ability to evolve implies the possibility of regression. Some B cells are going to be defective. Why are they not being discarded as they should be?

As I would understand it a B cell may be defective but wouldn't know. It would just see I'm doing something and hence multiply. It has no way of knowing what the impact is since it has no global view on the body. So to remove defective b cells you need an alternative mechanism - one is in the bone marrow which gets them before they move out to the body but that can fail (particularly with certain genes) and I guess the other mechanism is to develop medicines such at Rituximab.

 

[Dx Revision Watch]

I'd suggest a new thread for discussion of BPS if no existing thread is suitable.

 

[MeSci]

The site you have referenced is a site maintained by Dr Jon Stone, Consultant Neurologist, Edinburgh.

I know - I have done some searching about him - he has some associates whose names will be horribly familiar here.

 

[Jonathan Edwards]

I hope you agree that a physician needs to consider non-medical issues even if considered secondary to proper medical treatment?

Absolutely. For the first twenty years that I looked after people with RA my job was largely one of managing psychological and social issues - as a physician. I wouldn't even consider these non-medical really. Medicine is about trying to solve life problems, not blood results. But we never talked of a 'biopsychosocial model'. And I agree with A.B. that 'the BPS model' of ME does not exist - how can it when we have no clue what is going on - no substantiated theory. We have no reliable data for causal effects of psychological or social factors. It is just insinuated that there must be. This is bullshitting.

My book-writing analogy for autoimmunity is just as applicable to brains. In at least some cases ME might be a 'software crash' purely in the brain. But that does not mean there are 'psychological or social causes'. One has to consider the scenario as a whole. The cause is really the way the world is. We do not have the option to hop in the Starship Enterprise and nip off to the emotionally sanitised atmosphere of Vulcan (because Kirk has taken it for a millenial service).

I think MS provides a useful comparison here. MS patients get supportive advice about recovery from their neurologists (hopefully). They also get exercises from physiotherapists. What is not said is that these therapies are designed to work by suggestion, as in the placebo effect, despite the fact they obviously will do to an important degree. Nobody talks of 'MSBT': an unsubstantiated specialised technique that uniquely gives the best placebo effect for MS and induces recovery.

The key difference is the perception that MS pathology causes impaired function in the brain at a level below that of 'mind'. It does of course effect mind, though, so the involvement of mind is not what matters. The key difference, I think is that it is assumed that in MS the regulatory errors caused by the disease are not correctable through the 'psychological' means of talk and body language. (Body language is almost certainly more important than talk, which is why I suspect that many therapists delivering CBT in word terms are completely useless even as placebos - often the reverse.) The assumption of the BPS model is that the regulatory errors of ME are susceptible to language.

I am prepared to believe that some people who have the symptom complex of CFS and might even be said to have an ME have brain regulatory errors that are indeed susceptible to language. Language can have extremely powerful effects on deep brain mechanisms. 'Miracle cures' in church are perfectly within the realm of neurophysiology. But what strikes me as indisputable is that for the great majority of people with ME/CFS this does not seem to apply. There are regulatory errors in brain, immune system or both that are completely unreachable by tweaking endorphine receptors with language. They are at a different level of biological structure - a level that is not 'mind' in the sense the ordinary person understands.

Maybe the real contradiction in the 'BPS model' is that it is propounded as 'a model' while at the same time it is acknowledged that there are a wide range of different 'diseases' involved. We do not have a breakfastlunchdinner model for a meal. It is either breakfast or lunch or dinner or maybe brunch.

Apart from getting involved in ME I spend most of my time researching the structure of the mind. As you might expect my views are precise, complicated and quite different from the received wisdom (that's being a Vulcan for you). The mind is far more magic than magic but I think it is also something we can understand in a scientific way. Like a newborn baby it is the most wonderful thing of all but it still has to be bathed and dressed and looked after because it is in fact helpless on its own. It cannot undo a plaque of demyelination in MS and similarly I do not think it can undo most types of ME process.

So I cannot take 'biopsychosocial' seriously. Like Maria Fitzgerald I would like to go for 'all biological'. Whether we agree what we mean by that is another matter, and hopefully I will find out when we meet for lunch in a few weeks time.

 

[Sasha]

I'd suggest a new thread for discussion of BPS if no existing thread is suitable.

I'm away for five minutes...

I had a visitor yesterday so haven't been following the thread and it looks as though we've gone off-course. I'll look over it and may get the mods to split the thread.

Meanwhile, please consider this a friendly shot across the bows - as I said in post #1, this thread is for a discussion of the science at the conference and shouldn't include general whacks at the involvement of the BPS school in in ME.

 

[Jonathan Edwards]

Dear Sasha,
For my part I think this stuff is all very relevant to the presentation of the BPS approach at the CMRC. We can avoid talking about 'schools' but I think what we are discussing really is the nitty gritty of the scientific question. As long as we play the ball not the man ...

 

[Sasha]

Dear Sasha,
For my part I think this stuff is all very relevant to the presentation of the BPS approach at the CMRC. We can avoid talking about 'schools' but I think what we are discussing really is the nitty gritty of the scientific question. As long as we play the ball not the man ...

I've just been going through it and some of it is a bit general and a bit tangential and I can see why people thought we had gone off-topic. But catching up, I get the sense that we've come back on track.

I'll leave things as they are for now - let's try to stick to the science, though, and not go into the politics or social implications. That stuff would indeed require a new thread.

 

[A.B.]

I am prepared to believe that some people who have the symptom complex of CFS and might even be said to have an ME have brain regulatory errors that are indeed susceptible to language. Language can have extremely powerful effects on deep brain mechanisms. 'Miracle cures' in church are perfectly within the realm of neurophysiology. But what strikes me as indisputable is that for the great majority of people with ME/CFS this does not seem to apply. There are regulatory errors in brain, immune system or both that are completely unreachable by tweaking endorphine receptors with language. They are at a different level of biological structure - a level that is not 'mind' in the sense the ordinary person understands.

I see little reason to believe that these alleged miracle cures are anything more than a strong placebo effect that temporarily creates a subjective sense of improvement. Do you have reasons to believe that they are actually cures?

Also, that a patient responds to a placebo doesn't mean that the problem was brain regulatory errors.

 

[Jonathan Edwards]

As I would understand it a B cell may be defective but wouldn't know. It would just see I'm doing something and hence multiply. It has no way of knowing what the impact is since it has no global view on the body. So to remove defective b cells you need an alternative mechanism - one is in the bone marrow which gets them before they move out to the body but that can fail (particularly with certain genes) and I guess the other mechanism is to develop medicines such at Rituximab.

That's how I would see it. Just as inside a computer the electrons have no global view of the fact they have crashed the software.

Another way to weed out bad B cells is with T cells, but the assumption is that in autoimmunity the T cells have been fooled as well as the bone marrow.

What I would dearly love to find is ways of telling just the misbehaving B cells to die. This is probably not science fiction because it is probably possible in myasthenia. In myasthenia B cells set up shop in the thymus gland, where they have no business to be. And probably the misbehaving anti-AChR B cells set up shop there. A lot of patients with myasthenia have their thymus taken out. Interestingly, the myasthenia does not go away immediately but in maybe 70-80% of cases, according to Dr Angel Vincent, it eventually dies down. That would fit with the eventual dying off of anti-AChR plasma cells that have gone to bone marrow, where they may live for 5-10 years. If no more B cells are growing up in the thymus that may be the end of that.

It would be fantastic to find a way of telling the misbehaving rheumatoid factor and anti-CCP B cells in RA to die, leaving all the others alone. Maybe one could trick the CCP B cells with some 'dud CCP' - a sort of competitive antagonist. It may be that gold and penicillamine worked in RA by confusing the rheumatoid factor B cells by stopping the RF complexes from binding to receptors or something, but they were too toxic. If some sorts of ME are dependent on particular types of antibody then it is just possible that we might find a way to remove those leaving the others alone, but that is a long way off even if it turns out to be realistic.

 

[Jonathan Edwards]

I see little reason to believe that these alleged miracle cures are anything more than a strong placebo effect that temporarily creates a subjective sense of improvement. Do you have reasons to believe that they are actually cures?

I agree. I suspect most reported miracle cures are even not even that. I am just saying that nothing is quite black and white here, although it is certainly not a one-fits-all murky grey as some would suggest.

Also, that a patient responds to a placebo doesn't mean that the problem was brain regulatory errors.

Absolutely. The pain of arthritis can respond to placebo and that pain is either due to an immune regulatory error or maybe just a worn out joint. I like to think of ME in regulatory error terms because that would make it hopefully completely reversible. If something is worn away you don't have that chance, even if you can do a joint replacement.

 

[MeSci]

A lot of patients with myasthenia have their thymus taken out. Interestingly, the myasthenia does not go away immediately but in maybe 70-80% of cases, according to Dr Angel Vincent, it eventually dies down. That would fit with the eventual dying off of anti-AChR plasma cells that have gone to bone marrow, where they may live for 5-10 years.

Does this 5-10-year lifespan apply to autoantibody-producing plasma cells generally? I was thinking that if one could somehow switch off the initial creation of these illness-causing/perpetuating cells, an illness might take 5-10 years to gradually resolve.

Sorry if this is a stupid question but my brain is on the verge of going on strike!

 

[user9876]

I am prepared to believe that some people who have the symptom complex of CFS and might even be said to have an ME have brain regulatory errors that are indeed susceptible to language. Language can have extremely powerful effects on deep brain mechanisms. 'Miracle cures' in church are perfectly within the realm of neurophysiology. But what strikes me as indisputable is that for the great majority of people with ME/CFS this does not seem to apply. There are regulatory errors in brain, immune system or both that are completely unreachable by tweaking endorphine receptors with language. They are at a different level of biological structure - a level that is not 'mind' in the sense the ordinary person understands.

The question would be what paths do thoughts have to influence the brain mechanisms and the body (is this always via endorphins?).

We also need to take care that language doesn't just change how things are reported. Personally, I would separate out language from mental representation both have semantic and compositional structure but they are not necessarily equivalent. Language becomes a communal thing in that not everything is said but there is a lot of assumed knowledge between two people talking. The problem comes where we don't have accurate words to express concepts in the mental representation we can try to describe them. However, suggesting certain words to describe symptoms can then lead to a great deal of lumping between patients. For example, things like PEM and fatigue are they words different people use to describe the same experience or do they describe different experiences but form a useful word to communicate the internal representation of an experience that would otherwise be hard to explain or take a long time.

I remember going to talk many years ago where someone was talking about language and some of the effects that a stroke could have. One story I remember was about a patient who could conceptualize and describe a cabbage but couldn't remember the word for what it is. Hence the separation of language from mental representation.

I guess I have two points:
1) Where symptoms are self described then by suggesting language to describe things do we get symptom clusters that may be differentiable if the concepts are broken down in more detail.
2) Where we suggest language to describe things we can get reporting effects without changing the underlying experience so that people may learn to use different language to describe the same thing. I wonder if CBT therapists see some of this type of effect.

 

[Jonathan Edwards]

Does this 5-10-year lifespan apply to autoantibody-producing plasma cells generally? I was thinking that if one could somehow switch off the initial creation of these illness-causing/perpetuating cells, an illness might take 5-10 years to gradually resolve.

Sorry if this is a stupid question but my brain is on the verge of going on strike!

Actually that is a nice point. The work with rituximab suggests that a lot of illness-causing autoantibodies are produced by plasma cells that only last a few months - hence the improvement after 3 months. But in other situations the plasma cells seem to go on longer - for instance those making anti-RNP antibodies in lupus. It would be good if any relevant plasma cells in ME were 3 month ones - at least the Norwegian results might point in that direction. My impression is that in myasthenia thymus removal helps quite a lot quite quickly but full resolution of the disease takes longer. That would fit with the plausible scenario that plasma cell lifespan varies across a spectrum - which we know it does at least in some situations.

 

[daisybell]

And if the language for something does not exist, then sometimes the concept also is not recognised.... This is how different cultures with different vocabulary can misunderstand each other so completely. I would agree that the terms 'fatigue' and 'malaise' are problematic for us. These are understood to an extent by most well people, but I don't think that the experience of either in ME bears any relation to the experience of them by normally well people. Certainly that is my experience.

 

[user9876]

T

What I would dearly love to find is ways of telling just the misbehaving B cells to die.

I read an article a little while ago about a new leukemia treatment where they were training the immune system to recognize the leukemia cells and hence destroy them.

http://www.mskcc.org/blog/new-trial-advances-cell-based-immune-therapy-certain-leukemias

They talk about removing T cells and introducing a new gene that attacks the cancer cells. I don't know if that could be done with auto immune diseases.

 

[alex3619]

Deletion of problematic antibody producing B cells is, I think, a problem. Deletion of such cells is not global, I forget the details of the science (or brain fog, one of the two) but its localized. Jonathon could say much more about this. However if target proteins are produced far from those areas, and are not expressed in those areas, the possibility has been raised that this may mean the B cells are not deleted. There was a paper on this mentioned on PR a few years back.

So the brain might express proteins not found in the Thymus or lymph nodes. Hence usual deletion processes might have failed. I think this might be a big issue in why so many autoimmune diseases target the brain. The protein or other targets are not involved in the B cell deletion process.

Now I think there are other corrective mechanisms, but again I cannot recall them. However they are likely to be much less effective and so will sometimes fail. Some of these are of course regulatory or suppression mechanisms, such as Tregs.

Darn, I need to go back and study my immunology again.

 

[surethom]

Personally I think the only way we can improve is when pharmaceutical companies create viable antivirals & immune boosting /NK drugs. So many people have been unwell after getting a virus & here in the UK u are unable to get I viral count or even if a virus is active!

 

[MeSci]

Actually that is a nice point. The work with rituximab suggests that a lot of illness-causing autoantibodies are produced by plasma cells that only last a few months - hence the improvement after 3 months. But in other situations the plasma cells seem to go on longer - for instance those making anti-RNP antibodies in lupus. It would be good if any relevant plasma cells in ME were 3 month ones - at least the Norwegian results might point in that direction. My impression is that in myasthenia thymus removal helps quite a lot quite quickly but full resolution of the disease takes longer. That would fit with the plausible scenario that plasma cell lifespan varies across a spectrum - which we know it does at least in some situations.

and maybe different MEs have different autoantibodies that have different lifespans.

Could it be that apparent non-responders to Rituximab just have longer-lived plasma cells that are difficult or impossible for the drug to access?