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

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Sasha wrote: "I think that natural selection is alive and well and that we can see it with ME. There are plenty of PWME here struck down before they had a chance to have kids."

Something about this is off to me, but I'm not sure how to think about it. To say "natural" selection doesn't seem quite right when you think of how much of our lives are socially engineered.

Maybe our huge human populations through social policy, including control of resources and media have created environments of selective breeding [artificial selection].
 
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Sasha

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Sasha wrote: "I think that natural selection is alive and well and that we can see it with ME. There are plenty of PWME here struck down before they had a chance to have kids."

Something about this is off to me, but I'm not sure how to think about it. To say "natural" selection doesn't seem quite right when you think of how much of our lives are socially engineered.

Maybe our huge human populations through social policy, including control of resources and media have created environments of selective breeding.
I understand your reaction but natural selection in the wild works through such selection pressures as fitness to be in sufficient health to find a mate and to be able to bear and provide for children. That's how you pass on your genes. Social policy can buffer us against those pressures to some extent but only so far. If you can't get out of bed or the house, you're not going to be able to find a partner or be able to bear or look after a child.
 
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...Social policy can buffer us against those pressures to some extent but only so far...
I'm thinking of social policy/social engineering/group behavior that harms individuals. - But it's not a big deal, and not to take the thread off topic.
 
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Marco

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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.
Another blog from Cort on recently published research showing underactivation of the basal ganglia and impaired dopamine metabolism :

These findings provide further evidence that inflammatory stimuli, including inflammatory cytokines, target basal ganglia and dopamine function to induce behavioral changes associated with inflammation in humans.
http://www.cortjohnson.org/blog/201...nflammation-fatigue-chronic-fatigue-syndrome/

A similar effect has been noted in IFN-gamma treatment of hep C.

His discussion is along similar lines to what we've been discussing here :

One of Miller’s earlier papers suggested that reduced dopamine uptake may leave the central nervous system particularly vulnerable to the negative effects of inflammatory processes. This bears repeating. Miller suggests reduced dopamine may be causing your system to get overly disturbed by whatever inflammation that is present. That could result in low levels of inflammation causing high levels of fatigue, motor slowness, cognitive problems, etc.

He’s not the first to suggest this kind of process is occurring. The Lights believe low signals of muscle damage are having an exaggerated effect, and Younger suggests that the microglia may be over-reacting to leptin in ME/CFS. In these scenario’s it’s the body’s reaction to a substance, not the substance itself, that is the problem.
 
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MeSci or Professor Edwards mentioned immunohistochemistry a few pages back. I did a quick search for immunohistochemistry on brain tissue in ME/CFS but didn’t find much. One study was reported in conference notes of a symposium on ME/CFS in Australia (page 14) of a single case of idiopathic encephalopathy. They examined the hippocampus, didn’t find activated microglia (instead reduced numbers and ‘suppression’), and detected Coxiella burnetti. It seems odd that microglia wouldn’t be activated if C. burnetti were present. Unlikely we are all suffering from Q fever so probably not that relevant anyway. A tissue/brain bank was discussed (page 12). Not sure if this eventuated. It was only a cursory search, but it was disappointing to find so little.

Immunofluorescence staining and confocal laser microscopy of brain tissue slices would provide more information about local cytokines (and the 3D images are pretty cool). Would need to narrow down what part of the brain to focus on though. Perhaps the PET study could help with that? Maybe someone has done this already, but hasn’t published yet, or didn’t find anything?

http://bond.edu.au/prod_ext/groups/public/@pub-burcs-gen/documents/genericwebdocument/bd3_018423.pdf

http://www.biomedcentral.com/1756-0500/7/370
 

Sasha

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@Jonathan Edwards - just thinking about this conference again and your comment that it was basically a neuroimmunology conference.

It was of course an ME-specific conference but presumably there are neuroimmunology conferences that have sessions of general interest and disease-specific sessions; and the same for conferences on rheumatology, immunology, neurology, endocrinology, gastroenterology and so on.

Given what you saw at this conference, and your (now apparently very wide!) knowledge of the ME literature, do you think that there's enough of a critical mass for researchers to be submitting papers and setting up sessions on ME in conferences in those disciplines?

One of the jobs we have to do is get the word out about this new ME science to other researchers and clinicians. An ME conference is one string to that bow but ME papers at other conferences could be another very powerful one.

Do you think we're there yet, science-wise?
 
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One of the jobs we have to do is get the word out about this new ME science to other researchers and clinicians. An ME conference is one string to that bow but ME papers at other conferences could be another very powerful one.

Do you think we're there yet, science-wise?[/USER]
I don't see why not, although I suspect ME specific conferences may actually be more important than the big speciality jamborees that are now so huge there is little or no real communication. Although a lot of the material in Bristol was neuroimmunology, much of that was not specifically about ME - it was more of interest as a model for thinking about ME (things like alpha interferon fatigue). I suspect that if the same papers were presented to large meetings they would be rather spread around the specialities. But if something really exciting comes out of one of these studies I see no reason why it should not do the rounds of a number of speciality meetings - immunology, neurology, rheumatology etc.[/user]
 

Sasha

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I don't see why not, although I suspect ME specific conferences may actually be more important than the big speciality jamborees that are now so huge there is little or no real communication. Although a lot of the material in Bristol was neuroimmunology, much of that was not specifically about ME - it was more of interest as a model for thinking about ME (things like alpha interferon fatigue). I suspect that if the same papers were presented to large meetings they would be rather spread around the specialities. But if something really exciting comes out of one of these studies I see no reason why it should not do the rounds of a number of speciality meetings - immunology, neurology, rheumatology etc.[/user]
That would be great to see something escaping the confines of the existing ME research/clinical community.

I think a group of ME-specific papers within a speciality conference might actually be quite a draw - novelty is always attractive! Especially if the field is presented as a frontier-busting challenge, which it is, in many ways - if this were an easy problem to solve it would have been done by now.
 

wastwater

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I have a rare genetic disorder and see glial cells mentioned a lot in connection with it,that's why I think microglial way of thinking is going in the right direction.I was surprised to find so many people with fatigue states in my group.My crude understanding of this is that cytokines are higher than normal and setting off the glial cells inducing a kind of resting state/sickness behaviour.
 

nandixon

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...In a sense I think what the Norwegians and the group at UCL may be trying to pin down with B cell work is whether we are dealing with just some processes that I called ME3 - loops set up in the CNS - or whether there are continuing antibody-mediated loops, of the ME5 sort, keeping ME3 going. Rituximab responders may be those for whom block of ME5 allows ME3 to fizzle out. Non-responders may have a more entrenched ME3. ME3 may still involve activated microglia, and in that sense be 'immune' but it may be independent of B cells. The same might apply to ME2, which would stand in for ME5 maybe through a T cell mechanism...
Under an inappropriately activated microglia theory, it seems that ME3 and ME5 might overlap. But what I was actually writing about is, could the timing of the response (and relapse) cycle seen with rituximab in ME/CFS be corresponding to not only a depletion of the B-cells but also a gradual deactivation (or reduction in numbers) of microglia that may be inappropriately chronically activated because of a particular B-cell (or -cells) they are receiving exposure to? (Edit: This might be what you're meaning as I reread your post.)

Under this idea, the problem rituximab might be attempting to correct may not be so much a bad B-cell but rather bad microglia that are having an inappropriate response to a B-cell. If that's the case, then perhaps some adjunct treatment for the microglia might be useful to accelerate the person's getting better with rituximab. (For example, inhibition or even depletion of the microglia as mentioned here:
http://forums.phoenixrising.me/inde...icroglial-inhibitors.34164/page-3#post-540169)

Under an umbrella microglial disease theory for ME/CFS, that might also explain why some people don't respond to rituximab, i.e., it would depend on whether the person's inappropriately activated microglia had been sensitized to the effects of a B-cell, or whether the activation was due to some other non-B-cell stimuli - of which there seem to be quite a few in the case of microglia.

This article suggests how B-cells might affect microglia:
High-fat-diet exposure induces IgG accumulation in hypothalamic microglia
http://dmm.biologists.org/content/5/5/686.full
By contrast, highly activated microglia release cytokines to recruit or stimulate more microglia and even lymphocytes, such as B cells and T cells, into the ARC (Persidsky et al., 1999; Nelson et al., 2002). Recruited B cells could therefore produce antibodies locally in the ARC. Thus, the IgG accumulation could be the cause, but also the consequence, of microglial activation, and these two processes might eventually turn into a vicious cycle. Such a process would increasingly influence the microenvironment of the ARC and possibly damage other cell types in the ARC.
 
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As JE keeps stressing though, the kinetics of the recovery pattern from Rituximab is important. The recovery patterns seem to reflect the depletion of antibodies over time.

Studies like the following only run for 12 days, and CFS patients did not recover in just 12 days (or 2 months):
"Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241793/

It is hard to see how depletion of antibodies (Which takes longer) can contribute to that, unless there is a less direct (but still important) pathway between antibody depletion and microglia activation.
 

nandixon

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The way I was thinking about it (which may be wrong) is: Say we are talking about the problematic microglia being in the hypothalamus. Then once rituximab has done its job in a ME/CFS patient and eliminated all the B-cells, even though now there are no more offending B-cells to cross the blood-brain barrier there still may be microglia left that effectively have a long-term memory because they are associated with memory T-cells. So the microglia continue to remain activated to some degree until they die. (And it seems they probably have a lifespan at least as long as macrophages, i.e., 100 days, if I understand correctly.)

Something along the lines of:
Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204167/

On another note, I'm not sure how well rituximab can cross the blood-brain barrier absent a BBB disruption technique. And after seeing the article you cited, and seeing how rituximab can decrease microglial activation, I wonder if it might be useful to use BBB disruption with the rituximab infusions, if they aren't doing so already, similar to what is described here?:
Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances
http://www.ncbi.nlm.nih.gov/pubmed/25307218/
 
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Under an inappropriately activated microglia theory, it seems that ME3 and ME5 might overlap. But what I was actually writing about is, could the timing of the response (and relapse) cycle seen with rituximab in ME/CFS be corresponding to not only a depletion of the B-cells but also a gradual deactivation (or reduction in numbers) of microglia that may be inappropriately chronically activated because of a particular B-cell (or -cells) they are receiving exposure to? (Edit: This might be what you're meaning as I reread your post.)

Under this idea, the problem rituximab might be attempting to correct may not be so much a bad B-cell but rather bad microglia that are having an inappropriate response to a B-cell. If that's the case, then perhaps some adjunct treatment for the microglia might be useful to accelerate the person's getting better with rituximab. (For example, inhibition or even depletion of the microglia as mentioned here:
http://forums.phoenixrising.me/inde...icroglial-inhibitors.34164/page-3#post-540169)

Under an umbrella microglial disease theory for ME/CFS, that might also explain why some people don't respond to rituximab, i.e., it would depend on whether the person's inappropriately activated microglia had been sensitized to the effects of a B-cell, or whether the activation was due to some other non-B-cell stimuli - of which there seem to be quite a few in the case of microglia.

This article suggests how B-cells might affect microglia:
High-fat-diet exposure induces IgG accumulation in hypothalamic microglia
http://dmm.biologists.org/content/5/5/686.full
I have just caught up with this discussion. You are right that persistent microglial activation might contribute to the prolonged response time to rituximab. However, the article you quote I think may be a red herring. B cells very rarely enter the CNS. Multiple sclerosis is very unusual in this respect. I have always thought that in MS B cells in the CNS would activate microglia and form a vicious cycle as suggested in this paper but I can only see this applying to MS.

B cells are not inflammatory cells, unlike T cells and macrophages. B cells get involved in a lot of signalling in lymphoid tissues but are not effector cells - it is their daughter plasma cells that do the effecting via antibody. Plasma cells do get into inflammation, but B cells only survive there in a few odd types of pathology - including MS for the brain, RA for joints and myasthenia for thymus. When B cells get into brain you get demyelination and plasma cell maturation with oligoclonal Ig - i.e. you get MS. That would not be relevant to ME I think. I don't think microglial activation in ME would be associated with B cells in brain, so it seems it would really have to be driven by circulating antibody - and so we are back to the explanation based on antibody kinetics or just a coincidence that both antibody and microglial activation take months to decline.

I hoep that makes sense. Things may be more complicated than I am suggesting but I am sceptical of studies purporting to show some antibody-independent mechanism for rituximab. A lot of people's grant funding depends on maintaining the fiction that there are autoreactive T cells in human autoimmunity and so they are desperate to find reasons why rituximab affects T cells. I think in the case of the rat paper Snow Leopard quotes they may have shown that their model is not antibody independent after all!
 

Kati

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It is important to me that we understand the pathophysiology of ME and that further studies on Rituximab occur, including
1) Do responders have a durable response and also a response that dramatically improve their quality of life, like being able to return to normal activities like working for instance.

2) do non-responders have a different pathology, or disease beyond the B-cells (CD-20) or simply the disease could not reach out the CNS

3) could certain drugs be injected in the Cerebro-spinal fluid in order to access the CNS?

4) is Rituximab an adequate treatment and does it compare to Ampligen or Anti-viral in ME patient?

Currently, we are not even sure of the exact pathology. We have inflammation, we have brain changes, we have pain and so far (with studies being panned or already underway) we only have a publication of 15 pts/ 15 placebo study results to go from.