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

[Bob]

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.

Indeed. And it's promoted as the model for all unexplained chronic fatigue (i.e. the Oxford criteria), not just CFS/ME. So, supposedly, every single person in the world, who suffers from unexplained chronic fatigue, is ill because of a fear of exertion, and deconditioning. The model itself is a logical fallacy.

 

[Marco]

@Jonathan Edwards

You may have already explained this and apologies if you have.

To use your analogy, what happens when you have a best seller that isn't Mein Kampf when the pathogen or whatever has been cleared?

Also, if I picked it up correctly, the error in the immune system isn't with distinguishing self from non-self but the perpetuation of the immune response? If that's the case you should also occasionally get a similar error but one which is targeted at a pathogen which isn't there any more? Would this have any consequences?

Probably got the wrong end of the stick here.

 

[Jonathan Edwards]

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?

Certainly.

 

[Jonathan Edwards]

@Jonathan Edwards

To use your analogy, what happens when you have a best seller that isn't Mein Kampf when the pathogen or whatever has been cleared?

Also, if I picked it up correctly, the error in the immune system isn't with distinguishing self from non-self but the perpetuation of the immune response? If that's the case you should also occasionally get a similar error but one which is targeted at a pathogen which isn't there any more? Would this have any consequences?

Probably got the wrong end of the stick here.

No, I think that's relevant. If it was a best seller because it was so relevant to the issues of the times, even if the times change over the years it is what we call a 'Jane Austen' and continues to be produced as part of an elegant Folio Society 'Classic Plasma Cell' series. And decades later it is not unusual for people to read it and say 'it is still relevant today' - and that is the reason why we do not catch chicken pox from schoolkids on the bus very often. These plasma cells never go out of print. But there are also major works that do go out of print - the plasma cells die off after 5-10 years (like Bertrand Russell's Analysis of Mind) - but then someone says we better do a reprint because the students still need to have read it - and that would be tetanus booster vaccination for agricultural workers.

Things are actually quite complicated and not fully understood for things like zoster virus because it remains hidden in a lot of us and can reappear as shingles if plasma cells die off enough (or maybe the T cells get lazy).

I guess it is that the self-non-self discrimination comes at the point of deciding whether to let a B cell persist and multiplpy. But as various people have pointed out, there are multiple steps in this, with vetoing of anti-self in bone marrow, T cell areas and follicle centres as well.

So the question is whether or not you get multiplication of B cells that is 'inappropriate' not in the sense of being anti-sefl but against a pathogen that isn't around any more. That would be quite hard to envisage because the multiplication stage does need antigen to be around usually. It needs two signals - antigen plus 'permission to respond'. With no antigen at all the cycle is unlikely to occur. Nevertheless, there is a peculiar situation in lupus. It seems that in lupus the B cells are allowed to do what they like. As a result some become autoimmune. Also they do not take proper notice of pathogens so infection is a big problem. More weirdly, lupus patients can have antibodies to antigens they have never even seen, and a case in point is rituximab, because lupus patients can have antibodies against rituximab without ever having had it before. It is almost as if the whole thing has just become random with no selection going on.

 

[A.B.]

If Rituximab shows that ME/CFS is an autoimmune illness in some cases, what are the antibodies directed against, and why haven't they been found?

 

[Marco]

I guess it is that the self-non-self discrimination comes at the point of deciding whether to let a B cell persist and multiplpy. But as various people have pointed out, there are multiple steps in this, with vetoing of anti-self in bone marrow, T cell areas and follicle centres as well.

I struggle with this notion of self/non-self which suggests that the immune system is just there patrolling and ready to wage war on any 'outsiders' compared to the fact that we harbour more non-self than self and the body (self) we have today won't be the same one (cellular wise) in a month's time and god forbid we get pregnant. I rather like the idea (not that that matters) that rather than a body we are a 'pattern' and the immune system's job is to maintain the cellular integrity that conforms to that pattern rather than fighting invaders. The upshot of which might be that the immune system regulates the proliferation of cells that are both 'self and non-self' and 'infection' may be tolerated within certain limits. Wooly new age nonsense possibly but has a certain appeal.

So the question is whether or not you get multiplication of B cells that is 'inappropriate' not in the sense of being anti-sefl but against a pathogen that isn't around any more. That would be quite hard to envisage because the multiplication stage does need antigen to be around usually. It needs two signals - antigen plus 'permission to respond'. With no antigen at all the cycle is unlikely to occur.

Presumably you will have some of these long duration B cells still in circulation for a while which makes some sense (anthropomorphologically) in terms of the precautionary principle.

PS - Ouch - Lupus sounds rough.

 

[jimells]

to my mind 'inflammation' is no longer of any use to us as a concept in the context of MEs. Inflammation is a very curious rag bag concept. It is most obviously about swelling due to increased vascular permabiity and influx of white blood cells. ...Inflammation is a rubbish term we need to bin. The whole debate is at a level too low to get us anywhere.

Rant over.

What an informative rant! I've noticed that the term "inflammation" seems to be used in two very ways, without any specific mention of this: 1) swelling, etc. response to injury and 2) the immune system response to invaders. I assumed using the same word for both processes was just some sort of archaic terminology that medical people all understand.

Now it appears that the word "inflammation" is indeed archaic, but in reality medical people are confused over what it actually means.

I'm glad to know I'm not the only one confused!

 

[MeSci]

@Jonathan Edwards, some of your surreal analogies had me laughing out loud. Very creative!

What with that and @Marco's 'New Age Nonsense' I am tempted to ask what you are both on, and can I have some?

 

[Jonathan Edwards]

If Rituximab shows that ME/CFS is an autoimmune illness in some cases, what are the antibodies directed against, and why haven't they been found?

It might be that in those people with ME and antinuclear antibodies (maybe 10% of ME) they have been found. Otherwise the fact that they have not been found should perhaps not be too surprising. Previously unrecognised autoantibodies are still regularly turning up. For the rare diseases with antibodies to potassium channel complex components these have only been sorted out very recently. Even for diseases like rheumatoid arthritis some of the autoantibodies have only been characterised properly in the last fifteen years and there may be more we do not know of.

But there is a significant possibility that any autoantibodies in ME might be of a sort that does not show up on the usual tests. I have previously mentioned the possibility of antibodies being prebound to the receptor FCR1 (CD64). These may have a much lower binding affinity for antigen and not show on usual tests. They might even be like the antibodies in MS, where nobody really knows if they are 'auto-' or just being made in the brain when they shouldn't be. I t may be that even antibodies to 'flu' made in your meninges can give you more than just a bad headache.

So there are lots of possible answers, but no very clear indication if any of them are right as yet.

 

[Strawberry]

Things are actually quite complicated and not fully understood for things like zoster virus because it remains hidden in a lot of us and can reappear as shingles if plasma cells die off enough (or maybe the T cells get lazy).

Would that mean that this virus would be a good place to start researching? It is pretty obvious when it reactivates as shingles, unlike the other viral activated triggers in ME/CFS and MS. Could the pathways be similar?

 

[jimells]

This is why I get very cautious about these 'one size fits all' approaches to solving questions. 'Neuroinflammation' is trendy. Ageing is trendy. Let's write a paper on neuroinflammation in ageing and get a few grants in (and citations for the annual research audit).

It is so gratifying to read such candid comments (that reflect my own views) from a seasoned researcher! It almost makes me think that maybe my cynicism really is justified, that I'm not just a curmudgeon (although I would never deny that I am, indeed, an old curmudgeon).

I'm dismayed to think about all the resources and talent used to produce the useless research we've been inundated with. But I'm not going to think about that today. Reading about the honest dedicated researchers at this conference, all working on our behalf, gives me a reason to think that maybe I'll live long enough to see real treatments for this illness.

 

[jimells]

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.

I believe that whatever is wrong with me is reversible, for the simple (simplistic?) reason that I have had a number of partial remissions. In 2008 I was almost back to 100% for a few months. I was able to set up forms and pour concrete for my basement, jack up my trailer house for transport, and set it up on the foundation.

Alas it didn't last. Now I can barely get to the grocery three or four times a month.

 

[Jonathan Edwards]

Would that mean that this virus would be a good place to start researching? It is pretty obvious when it reactivates as shingles, unlike the other viral activated triggers in ME/CFS and MS. Could the pathways be similar?

I am not sure that zoster reactivation is of much interest. It mostly happens later on in life presumably when antibody levels have faded out over many years. ME does not seem to be like that and there does not seem to be much evidence for viral reactivation anyway as far as I can see.

 

[Jonathan Edwards]

I'm dismayed to think about all the resources and talent used to produce the useless research we've been inundated with. But I'm not going to think about that today.

A lot of research turns out to lead nowhere much but since we never really know which will be the best direction I would not be too hard on the research itself. What I find disappointing is that sometimes quite good research is done but the interpretation is mindless because people think the main objective is to agree with what is trendy.

In this regard I am having another look at the Japanese PET scan paper we have been mentioning. It is entitled:
Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. I am beginning to think that this may be a really important step forward in understanding brain abnormalities, but as far as I can see it has nothing whatever to do with inflammation. It is a thousand times more interesting than just finding the same old 'I' word in a brain. It shows something present in normal people that seems to be increased in ME and it is in a very specific small part of the brain close to the brain stem. It is picked up by tagging a specific translocator protein. I am going to sit down and read it through again carefully when I get time later today.

 

[MeSci]

The reason for thinking of CD64 goes like this. There are three Fc receptors (of interest here), conveniently named by powers of 2 CD16, CD32 and CD64. CD16 and CD32 have moderate affinity for antibody. This means that if they find a soluble antibody molecule they cannot really be bothered to bind to it for more than a picosecond. But if antibody is already immobilised on an antigen as part of an immune complex CD16 and CD32 will bind stably and fire out cytokines from the macrophage.

Antibodies that can form immune complexes on their own must have high affinity for their target antigen and so ought to show up on immunofluorescence tests of patient serum put on to neural tissues. In ME nobody may have looked properly but it is likely that if they were there someone would have noticed by now. So if microglia were binding to immune complexes through CD16 or CD32 we ought to have found the autoantibodies. There is also the point that these receptors, particularly CD16 generate a brisk TNF response and there is no brisk TNF response anywhere else in ME. If there was there would be a raised CRP. Add to that the fact that only macrophages in a few tissues use CD16 and it looks as if microglia are not on the list. If they were people with RA would have encephalitis.

So this leads us to consider CD64, which is a bit of an 'orphan' receptor because nobody understands why it wants to bind soluble antibody with high affinity. It will get gummed up with any old antibody, regardless of whether there is any antigen around. But a reasonable answer is that it is there to bind nonspecific 'natural' antibody that might be useful right at the beginning of an infection. This time the immobilisation of the antibody that increases stability of binding will be the receptor-antibody link (for CD16 it is the antibody-antigen link). Another feature of CD64 is that it is specifically regulated by gamma interferon, which is a signal used in early intracellular infection.

That is probably enough to give an idea why I think CD64 might be the 'invisible go-between' in ME. If not properly regulated it can cause trouble using ordinary natural antibody rather than needing high specificity autoantibody. And for CD64 the priming would be a specific gamma IFN priming, not an LPS or TLR priming. That is why I am so keen to get this specific and not just talk of 'neuroinflammation'.

Sorry if this has already been answered (it's a huge thread and my ME brain has limited capacity) but I am particularly interested in the gamma IFN aspect. Was it Hornig who observed in a paper that it was high in the first 3 years of ME and (normal?) later? And people seem more likely to recover in the first 3 (or so) years than if they have been ill for longer.

Can you posit any possible mechanisms for the changes at around 3 years of illness, perhaps involving CD64?

 

[user9876]

Sorry if this has already been answered (it's a huge thread and my ME brain has limited capacity) but I am particularly interested in the gamma IFN aspect. Was it Hornig who observed in a paper that it was high in the first 3 years of ME and (normal?) later? And people seem more likely to recover in the first 3 (or so) years than if they have been ill for longer.

Can you posit any possible mechanisms for the changes at around 3 years of illness, perhaps involving CD64?

I've wondered about Hornig's results around the 3 years but I've not seen the detail. I guess I'm wondering is there a significant subset of people who have different measures in the 1st three years and then get better or is there a genuine change after 3 years. If say x% the people in the under 3 year group were to have something different say around different gamma IFN levels then there would be a threshold for x to create a significant result for the overall group. Where as the other y% in the under 3 year group could match those in the over three year group.
The alternative would be a switch in disease mechanism which would presumably tell us something interesting?

 

[Jonathan Edwards]

Sorry if this has already been answered (it's a huge thread and my ME brain has limited capacity) but I am particularly interested in the gamma IFN aspect. Was it Hornig who observed in a paper that it was high in the first 3 years of ME and (normal?) later? And people seem more likely to recover in the first 3 (or so) years than if they have been ill for longer.

Can you posit any possible mechanisms for the changes at around 3 years of illness, perhaps involving CD64?

I find it difficult to explain that and I agree with user9876 that we do not really know whether this is a change over time or two different lots of people.

 

[MeSci]

So, a simplistic possible scenario?

Infection causes production of gamma-interferon.
For some reason high levels of gamma-interferon persist.
At some point CD64 binds to non-specific antibodies on microglia/macrophages
Microglia/macrophages are thus primed and become overactive?

Struggling with memory as usual so may have got in a muddle!

 

[Jonathan Edwards]

So, a simplistic possible scenario?

Infection causes production of gamma-interferon.
For some reason high levels of gamma-interferon persist.
At some point CD64 binds to non-specific antibodies on microglia/macrophages
Microglia/macrophages are thus primed and become overactive?

Struggling with memory as usual so may have got in a muddle!

Something like that.

 

[MeSci]

Something like that.

Think I got that wrong - the CD64s are already on the microglia, and bind the antibodies, which primes the microglia?

Can't remember what happens after this - microglia overactive, I think. Oh my stupid brain...