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

[NK17]

With all this talk about the brain, I want to point out that there is also the gut. Many CFS patients report intestinal symptoms. A diagnosis of IBS is common.

In my experience, whenever I have intestinal symptoms, I also have increased fatigue, pain, concentration problems and mood problems. Since this tends to start after meals, the gut seems to be the starting point of these symptoms.

The gut also seems to play a role in the development of autoimmunity.

The gut and the brain are closely linked. Nowadays the gut is well recognized as the 'minor' brain on top of being extremely rich in immune cells.
I suffer of what I call intestinal headaches.
The two are absolutely intertwined.
Just wanted to point this out .
Also on top of the ME dx I've a dx of SIBO and autonomic dysfunction.
Because everything is connected, as the old latin say goes: "Omnia vivunt, omnia inter se conexa."
"Everything is alive, everything is interconnected." Cicero

 

[NK17]

Yes - the sort of PET scans used in the Japanese 'neuroinflammation' study are very expensive to perform

This is one of the reasons why, as a charity, we haven't been able to move forward with possibly commissioning someone reputable to look at repeating these very interesting findings

The neurological colleagues I have spoken to feel that this study is worth repeating

But if this is going to be done in the UK I think someone is going to have to apply to the MRC…...

Or else have these replicated @ Stanford by the Zinn's

 

[Jonathan Edwards]

@Jonathan Edwards
CD64 is constitutively found on only macrophages and monocytes, but treatment of polymorphonuclear leukocytes with cytokines like IFNγ and G-CSF can induce CD64 expression on these cells
Is this correct?

That sounds right to a first approximation. But my understanding is that microglia would be included in the 'macrophages', since they express CD68 and a bunch of other macrophage markers and have been seen as the brain equivalent in the past although recent work suggests they have a different lineage. And CD64 expression is not the same on all monocyte-macrophage lineage cells - it varies with microenvironment.

 

[lansbergen]

That sounds right to a first approximation. But my understanding is that microglia would be included in the 'macrophages', since they express CD68 and a bunch of other macrophage markers and have been seen as the brain equivalent in the past although recent work suggests they have a different lineage. And CD64 expression is not the same on all monocyte-macrophage lineage cells - it varies with microenvironment.

I always thought of microgla as brain macrophages for easy remembering.

 

[Snow Leopard]

I know that in some studies he uses DSM guidelines for the interview. When there's no known biological diagnosis, the interviewers are allowed to interpret physical symptoms as an indication of depression. And I do know that in at least one of those studies of his, patients weren't acknowledged as having a biological diagnosis for the purposes of the interview.

Hence I wouldn't be surprised if many of his study subjects are getting a depression label simply due to having physical symptoms which prevent them from doing fun stuff. Honestly, the only questionnaire or interview I can think of that would be of any use for assessing depression in patients with a chronic and disabling and marginalized illness would have just one question: "Are you depressed?"

Yes and unlike many other research groups, they actually tested different techniques:

http://www.tandfonline.com/doi/abs/10.1080/08870449808407452

Note that they used the SCID not the DIS in the aforementioned community based study.

 

[alex3619]

I wonder what would happen if we looked for activated macrophages in other parts of the body, or at least over-expression of macrophage markers?

 

[Marco]

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'.

Thanks. Can't fault your logic.

 

[Marco]

And I ain't buying that neither Marco. Actually, I think we are a bit at cross purpose and probably agree.

I think cross purposes is exactly the 'problem'.

You are looking for a novel specific mechanism that can explain an autoimmune basis for CFS - an autoimmune ME which I think we all expect will only apply to a sub-set of those diagnosed with CFS. Perhaps it will apply to a very substantial sub-set but it still leaves a proportion for whom autoimmunity isn't the answer.

I'm looking for a non-novel and non-specific mechanism that can explain not only the symptoms of ME/CFS but also why the symptoms of other 'complex multi-symptom syndromes' such as Gulf War Illness, post concussion syndrome and complex regional pain syndrome - that are obviously not autoimmune - often heavily overlap with or are indistinguisable from ME/CFS. For my purposes the notion of non-specific 'neuroinflammation' seems more logical than a series of specific but unrelated 'neuroinflammations'.

Both perspectives lead to the microglia as playing a key role.

 

[Jonathan Edwards]

This is a fairly recent review of the impact of aging on microglial response to immune challenge :

Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553257/

They suggest that microglial proliferation is limited to the specifc case of traumatic CNS injury and the enhanced 'proinflammatory' phenotype associated with aging is unlikely to be due to numbers. Microglia appear to be comparatively 'long lived' :

Impaired cellular repair mechanisms (e.g. in response to oxidative stress) appear to play a part.

Whether or not this activation is sufficiently large or persistent enough to be a useful model for ME/CFS is debateable.

I have had a detailed look at this and I have worked out what is wrong with it. Every sentence tells you what to think. A good science review tells you the data and points out uncertainties. This review tells you how you what to think before it even mentions the data - everything is gathered up into a journalistic story. Unfortunately, on the detailed science side it is clear that the authors have not got clear in their heads what the biological story is. The origins and shifts in function of microglia are clearly not as well understood as they portray. I know about this because my doctorate was on determining macrophage origins and the main conclusion was that it was difficult and complex.

They say that traumatic injury increases numbers of 'microglia'. What I do not think we know is whether these are more of the yolk sac population or an influx from bone marrow. (They give us a conflicting story.) They do not say anything about local accumulation during sensitisation by repeated nociceptor input for instance - which we were shown a picture of at the Bristol meeting. It does look as if in ageing numbers do not go up but maybe that is our answer - that what happens in ME is that numbers go up locally, maybe in basal ganglia, but in ageing you just get a shift in receptor expression, which may be largely due to replacement of yolk sac cells by bone marrow derived cells over a period of decades. And rodents would not be any good for this because their time span is quite different.

It seems to be a one size fits all again. Beware reviews in journals with posh names these days - they are largely journalistic I fear.

 

[Jonathan Edwards]

I think cross purposes is exactly the 'problem'.

You are looking for a novel specific mechanism that can explain an autoimmune basis for CFS - an autoimmune ME which I think we all expect will only apply to a sub-set of those diagnosed with CFS. Perhaps it will apply to a very substantial sub-set but it still leaves a proportion for whom autoimmunity isn't the answer.

I'm looking for a non-novel and non-specific mechanism that can explain not only the symptoms of ME/CFS but also why the symptoms of other 'complex multi-symptom syndromes' such as Gulf War Illness, post concussion syndrome and complex regional pain syndrome - that are obviously not autoimmune - often heavily overlap with or are indistinguisable from ME/CFS. For my purposes the notion of non-specific 'neuroinflammation' seems more logical than a series of specific but unrelated 'neuroinflammations'.

Both perspectives lead to the microglia as playing a key role.

No, Marco,we are indeed at cross purpose, but I think beginning to see the wood for the trees. I entirely agree that we are looking for a non-specific mechanism that might in some cases be fed into by autoantibodies. In other cases it would stand alone. And that would be a shift in microglial 'orchestration' in a broad sense. But it seems clear to me that we cannot invoke the changes seen in ageing. We need more than one sort of inflammation. You may not be familiar with the various forms of inflammation that have been well described even since the early twentieth century. As a student in 1970 I read about lots of different inflammations in Walter and Israel's Textbook of Pathology. The problem is that a lot of contemporary lab scientists are illiterate when it comes to the range of tissue microstructural changes. I had to take time out to train as a histologist to get up to speed on that. These stories in reviews simply don't add up. They become the 'received dogma' amongst those who like such things but solving ME needs specifics. We brought B cells back into RA science by pinning down one very specific subset of inflammation, involving CD16. ME cannot involve CD16, so we are looking for something just as specific - to my mind!

 

[Jonathan Edwards]

On another thread, @Sidereal posted some comments including:

I don't quite understand why this conference has people jumping with joy. We have been hearing this talk of sickness behaviour, inflammation, cytokines, microglia activation, interferon treatment for Hep C causing fatigue & depression etc. etc. since the 1990s in depression research, in particular the field of (psycho)neuroimmunology. Psych journals are full of this stuff. Go to any mainstream psychiatry conference and attend the depression sessions. The vast majority of the talks will be biological there too. You won't hear much psychobabble there either, the odd "out of place" talk maybe.

An enormous amount of money has already been spent (wasted) trying to figure out how these immunological concepts may translate into better treatments for depression-related fatigue and other symptoms and none of them - none - have panned out clinically thus far.

So forgive me if we're not all optimistic and grateful about these wonderful new developments in ME/CFS research.

Quite clearly (to me at least), fatigue in this disease is not the same as fatigue in other diseases, and we should be trying to figure out why that is. I have never once heard a patient with primary depression tell me that they went to a wedding and ended up bedridden for a week or a year as a result. Or that they did an exercise programme years ago and never recovered from it. They will tell you that they feel extremely exhausted and don't feel like doing anything but if encouraged to get out of bed and do things, they are not harmed by activity, and sometimes even feel better from it. We all know that this is not the case for ME-related fatigue. I can agree that immune activation can explain this perception of fatigue and pain and flu-like malaise but I don't see how the sickness behaviour / microglia activation hypothesis can possibly explain the total metabolic breakdown seen in ME, at least severe ME, where people struggle to even digest food or use their breathing muscles.

To summarise, nothing I've seen reported from this conference makes me think we will be in a situation any time soon where an ME patient goes to the GP and doesn't receive extremely harmful medical advice to increase their activity levels and thus slide deeper into disability. In fact, we could well be in the same place in another 30 years.

There is a lot I can agree with here. My initial reaction that the meeting was 'terrific' as much as anything reflected the fact that it was small, with lots of time for delegate chat, multidisciplinary, and for the most part excellent science, a good deal of which was new to me and would probably have been new to several other people who had moved into the ME field recently to do muscle metabolism, fMRI, HPA studies or whatever. There were some weaknesses, which I have at least hinted at.

The sickness behaviour story is certainly old, but what I thought was brought out particularly clearly by Carmine Pariante and Maria Fitzgerald in different ways was the fact that discrepancies in a broad brush view are emerging that might lead us to a specific answer for ME. Pariante pointed out that depression and fatigue are dissociated and Neil Harrison seemed to show that there were brain changes at the very onset of fatigue long before there were any mood changes. The real value of scientific meetings is in the arguments people have over coffee and there were plenty of those. None of this may be new to psychiatrists but it does seem to be new that we now have two major UK meetings in a year bringing all this stuff together for a group of people specifically interested in ME.

In 1990 we were in exactly the same position in RA we are now in for ME. An 'enormous amount of money had been spent' on immunological concepts with no results whatever. Then people like Ravinder Maini and myself started looking at TNF involvement. Tiny (Ravinder) beat us to it on that one but by the end of the decade we knew we had efective therapies with B cell depletion, IL-6 blockade and costimulation blockade. We also discovered that some other ideas did not work and that much of what had been done up to 1990 was indeed looking in the wrong place - but at least it got us there in the end. So I would not be quite so pessimistic. And to be honest I doubt any of this stuff has much to do with depression, so the failure on that front may be unrelated.

So I would absolutely agree with the point that fatigue in ME is not like 'other fatigue' - but that was the message I came away with from the conference, even if some older worthies would have it otherwise. But I think immune activation can do pretty much anything to any tissue, from muscle paralysis (myasthenia) to malabsorption (coeliac). We do not have a theory that completely hangs together, for sure, but that is the perfect situation to be in - because it means the answer must be something slightly different.

And I hear what you say about the gulf between any biological progress and the provision of care. Some things are not right, I agree. I am not sure it is my place to get involved but you have my full support on this.

 

[Valentijn]

But I think immune activation can do pretty much anything to any tissue, from muscle paralysis (myasthenia) to malabsorption (coeliac).

How would you explain immune involvement causing muscle paralysis? The mechanism for that is somewhat interesting to me, since I had my right thigh muscle completely stop working after walking a mile or two and standing for far too long in an airport when I hadn't been sick yet long enough to know better, combined with really horrible disability assistance.

I made it to my seat, but then couldn't stand up after we got up in the air when I needed to use the toilet. I could still move my right foot and some of the other muscles to wiggle my leg around a bit, and my left leg was working normally. But I couldn't lift my right leg at all, nor reposition it appropriately for standing up. Sensations were normal - no extra pain, I could feel it when I poked or messaged it, etc. And after an hour or so I was able to use it again. The muscle just seemed to be an unresponsive chunk of meat for a while.

 

[charles shepherd]

Or else have these replicated @ Stanford by the Zinn's

Yes - that might be worth pursuing…..

I met them in San Francisco in March

 

[Marco]

We brought B cells back into RA science by pinning down one very specific subset of inflammation, involving CD16. ME cannot involve CD16, so we are looking for something just as specific - to my mind!

I've been pondering what peripheral 'stressor' might be driving microglia. Neuropathic pain research suggests that ongoing peripheral nociception is required to maintain the central sensitisation. Objective findings of peripheral neuropathy in around 50% of fibromyalgia patients could be misdiagnosis or could be the peripheral driver in that condition. The problem as I see it with a specific inflammatory mechanism for ME is how loose and porous the case definitions are and the substantial symptom overlap with other conditions.

If you were able to determine a specific type of inflammation that might explain ME/CFS symptoms then you would have to consider the possibility that it also plays a role in similar symptoms in other conditions (not that that should be a problem) but I think we also need to consider the possibility that known inflammatory processes associated with other conditions could potentially lead to a diagnosis of ME/CFS in which case we might be looking for several specific subsets of inflammation. Back to this problem of little boxes/labels.

 

[Jonathan Edwards]

How would you explain immune involvement causing muscle paralysis? The mechanism for that is somewhat interesting to me, since I had my right thigh muscle completely stop working after walking a mile or two and standing for far too long in an airport when I hadn't been sick yet long enough to know better, combined with really horrible disability assistance.

I made it to my seat, but then couldn't stand up after we got up in the air when I needed to use the toilet. I could still move my right foot and some of the other muscles to wiggle my leg around a bit, and my left leg was working normally. But I couldn't lift my right leg at all, nor reposition it appropriately for standing up. Sensations were normal - no extra pain, I could feel it when I poked or messaged it, etc. And after an hour or so I was able to use it again. The muscle just seemed to be an unresponsive chunk of meat for a while.

Muscle paralysis in myasthenia occurs because antibodies to the muscle end plate (ACh receptor in the typical form but maybe a slightly different target in a second type) block nerve-to-muscle transmission.

The problem you had with the leg sounds to me like something a bit different. If it lasted an hour or so it probably has to be a temporary mechanical problem. Immune responses take longer. Pressure on a nerve could do something like this but not the nerve that tells your leg to lift. What I would personally suspect is a slight swelling of the lining of the hip allowing the lining to trap under a ligament. This may not in itself be noticed as painful and hip pain is not felt in the hip region anyway. But it can produce a total inhibition of nerve function - i.e. 'paralysis'.

And there could still be an immune response underlying this. This sort of thing can happen in polymyalgia, which can produce a subclinical hip synovitis, which would produce the sort of swelling that could lead to this type of nerve inhibition.

 

[Jonathan Edwards]

The problem as I see it with a specific inflammatory mechanism for ME is how loose and porous the case definitions are and the substantial symptom overlap with other conditions.

...I think we also need to consider the possibility that known inflammatory processes associated with other conditions could potentially lead to a diagnosis of ME/CFS in which case we might be looking for several specific subsets of inflammation. Back to this problem of little boxes/labels.

I am not sure we should be put off by loose definitions and overlap. For the first twenty years of my career I had to accept that rheumatoid and psoriatic arthritis were often completely indistinguishable, except for the presence of 'tell tale' skin and nail signs in Ps. Arth. The joint swelling is pretty much identical. But once we had treatments that distinguished the two it became clear that the underlying immunological mechanisms were quite different and that the local inflammation was being driven by quite different pathways. So in a sense the situation here was even worse than telling ME from other things.

I am not suggesting we are looking for anything other than known inflammatory processes. What I find a bit disappointing is the current tendency to ignore the fact that we know there are several different sorts. Microglial activation might be a homogeneous phenomenon but macrophage activation is not. In a joint a macrophage can turn into a 'synovial type A cell' or a 'tingible body macrophage' or a 'T cell zone macrophage' or a 'haemosiderin laden macrophage'. So there are four different 'activation' patterns in one tissue in one disease. In TB we get 'epithelioid cells'... the list continues. And in brain we have the complication that there are almost certainly two different populations by origin - yolk sac and bone marrow derived!

 

[Marco]

@Jonathan Edwards

I guess the point I was making was that looking for a specific type of inflammation may be analogous to the situation for several decades where researchers were looking for the pathogen that casued ME/CFS and as we know it turns out that just about any old common or garden virus can trigger ME in a small minority of folks and it is the immune response that appears to be the key. Likewise it could be 'any old' inflammation?

PS - I was intrigued by 'tissue microstructural changes'. Could these go unnoticed unless specifically looked for?

 

[Jonathan Edwards]

Yes, that point is well taken Marco, maybe we are getting around our confusions.

Tissue microstructural changes in brains could easily go unnoticed. Now that we have several fMRI techniques and PET they might start to show up but even so only indirectly because brain biopsy is just not a very good idea!

 

[Sasha]

Ian Lipkin: Microbiology and immunology of CFS/ME and other challenging disorders


Dr Lipkin gave a very wide ranging talk about the role of infectious agents and post infectious reactions in conditions including Sydenham’s chorea, AIDS, and herpesvirus infections. I actually think that many PR members will have accessed a video version of a similar presentation and will be familiar with Dr Lipkin’s work anyway. He mentioned the work on mice with PANDA like symptoms. He reviewed Dr Hornig’s recent studies on cytokines in early and late CFS/ME groups. It is certainly interesting that there seems to be a difference between patients with less than 3 years disease and those with longer disease for interferon gamma (again) and IL-17. Nevertheless, across the board the patients are not much different from controls so it seems pretty clear that the presence of any one of these cytokines in the blood cannot be held directly responsible for symptoms. CSF findings were also interesting in that IFN gamma and IL-17a tended to be lower.


Dr Lipkin discussed the importance of the microbiome and his plans for a large crowdfunded study. He also mentioned that some ‘hot data’ were coming out from Dr Hornig’s lab but said no more about this.

Apart from this small section of Dr Lipkin's talk (the study being crowdfunded is the one referred to in my signature), the microbiome in relation to ME doesn't seem to have featured in the presentations. However, there's a UK microbiota study currently being crowdfunded by IiME (led by Prof. Simon Carding) and this seems to be becoming an increasingly hot topic for ME (and medicine in general).

Without naming names (I'm not sure if conference attendees feel bashful about their attendance!), were you aware of any specialists in this area attending the conference, new networks forming, or coffee-break conversations in this area?

 

[Jonathan Edwards]

Apart from this small section of Dr Lipkin's talk (the study being crowdfunded is the one referred to in my signature), the microbiome in relation to ME doesn't seem to have featured in the presentations. However, there's a UK microbiota study currently being crowdfunded by IiME (led by Prof. Simon Carding) and this seems to be becoming an increasingly hot topic for ME (and medicine in general).

Without naming names (I'm not sure if conference attendees feel bashful about their attendance!), were you aware of any specialists in this area attending the conference, new networks forming, or coffee-break conversations in this area?

Not that I recall.