Is ME a metabolic problem or a signalling problem?

Thanks, agree that oxidative stress and low oxygen are 2 different things, however I go by conclusions made by researchers (quoted in my previous response)

Ref pro inf cytokines, you will find several studies showing increased levels of IL6 , TNF-A, IL1 B. So I would not agree that "there is no rise in inflammatory cytokines". You could find plenty of researchers who would say otherwise. However, robustness, consistency and definitive counts are lacking, and in my view this is largely due to heterogeneous subgroups, broad spectrum spread of this condition and other factors.

We all would love a "single piece of well established evidence", but I view this as very unlikely, given that this is not a one size fits all condition. Even the same person typically goes through remissions and relapses, during ebb and flow of this condition. So looking for one definitive "well established" biomarker may be difficult. It's just too fluid.

 

@butter.

Agreed. I view the present situation with ME research is that they're trying to figure out "one elephant"....but i think there may be "many elephants" (not just "one ME", but maybe several MEs). Rational sub grouping will help bring better focus and subtype specific research, which hopefully will translate into subtype specific treatments.

I'm afraid presently the field is bunching a number of subtypes together in studies and that will eventually not give good results.

 

If you are new here @Gdel you may not be aware that I am a retired professor of immunology and medicine at University College London and spent my life working on the inflammatory response.

I don't buy the evidence I am afraid.

One cannot afford to go by others' conclusions in science. We need to be able to asses the evidence because so much published stuff is rubbish.

I have seen none with clinically significant levels and most show nothing. The fact that CRP is normal is pretty conclusive evidence against any systemic inflammatory response. People will always try to find something positive in their results but basically there is nothing there.

Even if inflammation was limited to a subgroup it would have shown up. Maybe one person in twenty has some evidence of inflammation but they probably should not be diagnosed as ME.
I worked for many years on heterogeneous inflammatory conditions and I don't buy heterogeneity as an excuse for not finding things. If we do not have a single piece of established evidence we are still at first base.

 

Somewhat off topic @Jonathan Edwards but do you think there is a sub-group who have a B-cell autoimmune disease or do you think that those with a B-cell autoimmune disease "probably should not be diagnosed as ME"?

 

@Jonathan Edwards

Hi Prof Edwards, I was just going over your profile on ME Pedia...so you're definitely ahead of the game than most.

Agreed then, we are at base one.

 

Fair question. I am much less convinced of the possibility of a subset of ME being due to a B-cell based autoimmune process since the completion of the rituximab studies. The lack of effect of rituximab does not exclude the possibility but together with essentially negative studies on B cells I think the motivation for this line of thought is weak. I think there may be people with thyroid autoimmunity or Sjogren's syndrome who get put under an ME diagnosis and perhaps they come under 'should not be diagnosed...'.

I think a T cell based problem remains a realistic possibility. I doubt it would be strictly autoimmune but more like syndromes such as ankylosing spondylitis where there is probably a general T cell dysregulation, largely genetic.

But I think there is a difference between the B cell question and the inflammation question in that it is relatively easy to see how a B cell problem might be one of many feeding in to a more general process. It is harder to see inflammation as being one of many processes feeding into something like ME. If inflammation is only present in a small subset then a model for ME with inflammation at the centre won't fly.

 

Thank you very much for your reply.

Here's an extract from a recent response to an EU Parliamentary question on ME:
"Horizon 2020 funds --- RTCure(4) project that aims at improving diagnostics and treatment of the rheumatic and other autoimmune diseases largely associated with fatigue and pain."
[https://www.europarl.europa.eu/doceo/document/E-9-2019-002599-ASW_EN.html]

Yes, I agree, i.e. after the rituximab trial results it's difficult to see how a lot of people with ME could have a B-cell autoimmune disease. Interesting, and slightly worrying, that some people could have "thyroid autoimmunity or Sjogren's syndrome" and not be diagnosed - it's worrying that we still don't have reliable diagnostic tests for diseases.

 

I think these people are mostly diagnosed. The problem is that they may be wrongly led to believe that they ave two diseases when it is just one. Autoimmune disease can certainly produce major fatigue and in the case of thyroid autoimmunity this may not be change by hormonal adjustment.

 

I wonder what you think of Bhupesh Prusty's findings re mitochondrial fragmentation. I.e. filter ME plasma and add it to healthy cells the levels of mitochondrial fragmentation are normal. Add the material which has been filtered out (roughly size of exosomes) to healthy cells and mitochondrial fragmentation increases. Reminiscent of Ron Davis's observations and Fluge/Mella's observations - something in the blood.

 

Is there anything published on that?

 

I've noticed this myself among the online autoimmune groups that I am a member of. Before they get their AI diagnosis many people are labeled as having 'Fibromyalgia' or 'Chronic Fatigue Syndrome' (sometimes both as I was) and once they get their autoimmune condition diagnosed they hold on to the previous diagnosis instead of realizing that it's very likely that their previous dx was wrong and that the autoimmune issues are responsible for most if not all of their symptoms.

I never had any of my doctors say... "hey we should remove these old incorrect diagnosis from your list of medical diagnosis" and instead I had to bring it up and ask for them to be removed.

I remember how after my autoimmune conditions (Relapsing Polychondritis & Undifferentiated Connective Tissue Disease) were diagnosed I asked Jonathan Edwards about this very thing and his thought was that it most likely meant that my ME/CFS diagnosis had been wrong. Now after more than a year and a half of immune suppression medications and daily prednisone I have experienced very noticeable improvement in my fatigue and malaise (& PEM sx) compared to where I started at so in my case it's become very clear I never had ME/CFS. It's like night and day and there is no ambiguity as to whether or not the medications are working.

 

You've made me laugh.

I had an email from Bhupesh (there were a number of people in the correspondence - all more important) on 18th October "We are about to submit our manuscript on viral effects in ME/CFS". Hopefully that will be published fairly soon; however, your experience probably indicates that it can take a while to get a paper published.

I've sent a message

 

This is quite interesting. Mitochondrial fragmentation is a positive adaptive response to increased energy demands and oxidative stress.
https://www.ncbi.nlm.nih.gov/pubmed/29233845

 

Thanks @Snow Leopard "---mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling".

I wonder if this brings Bhupesh Prusty's work, where he appears to have found something in the blood i.e. causing increased mitochondrial fragmentation [NIH Conference April 2019], closer to Ron Davis's work (nano-needle impedance) something in the blood work? Also, Karl Morten's work --- increased oxygen consumption in muscle cells incubated with plasma from people with ME?

Also, I wonder if this will help to identify the factor in the blood i.e. if "β1-adrenergic receptor signaling" is the target. I think I recall that antibodies to adrenergic receptors were part of the theory re rituximab - that trial failed of course.

 

Does pyruvate dehydrogenase do a similar thing as alpha ketogluterate (SLC13a3)
Probably have reduced pyruvate via PITX2 PDP2
All genetically inherited would it come under inborn errors of metabolism or mitochondrial disease

 

Along the lines of auto brewery syndrome I wonder if there are other ones to be discovered like auto PCP syndrome ect

 

My physically-induced PEM had a consistent 24 hr delay. That fits with the rise in IFN-g that occurs after exertion. The IFN-g would trigger changes in glial cells, which in turn could cause the symptoms of PEM. Viral infections (I only had two since developing ME) caused the same increase in symptoms that physical exertion did. Increasing tryptophan transport into the brain also had the same effect, which convinced me that glial cells and kynurenines play a major role in my ME.

I also get PEM from cerebral activities such as driving (worse from stressful driving conditions) and socializing. This PEM feels the same, but has a more variable and much shorter delay, sometimes under an hour. That makes me think that physical exertion triggers delayed cytokine release, which on entering the brain, trigger the same processes that those cerebral activities do.

Physical exertion alone wasn't triggering my PEM. I could do hours of activities that my muscles were accustomed to, such as hiking or bike riding without triggering PEM. A minute or two of activities that used my muscles in non-accustomed ways, such as climbing a ladder, or washing an window (arms above shoulders was even worse) would trigger PEM. That convinced me that it was the cellular damage (torn cells) that triggered the t-cells to clean up the debris, and the cytokines from that triggered PEM.

 

To answer the original question, I believe that PEM, and ME overall, arise in the brain, with metabolic problems in the body as common--but not essential--downstream effect. My ME didn't involve any reduction in muscular strength or endurance, or any other indication of impaired mitochondrial function in my body. My symptoms are all neurological or explainable by downstream effects of neurological changes. Furthermore, I had several temporary remissions, where I seemed to switch from full ME to full health over the space of hours if not minutes (and then back again, just as rapidly). To me that suggests that the core dysfunction of ME is highly localized, such as a small clump of brain cells, rather than a whole-body alteration. More evidence: several of the treatments that worked for me were more effective if I took them sublingually, and blocking transport of tryptophan to the brain by taking BCAAs blocked the increase in symptom severity I would otherwise experience.

I expect that most body symptoms of ME could be explained by alterations in brain function. Small clumps of brain cells control all sorts of functions in the body, so small changes in those few cells could have major effects. Those brain cells in turn depend on glial cells to maintain their proper function, so they are sensitive to activation of the immune systems (the body has several semi-independent ones, and so does the brain). It seems plausible to me that an immune system activating event could trigger a change in the brain, which could alter the body in ways that make the immune system react more, forming a positive feedback loop that locks us into this ME state. I don't see why altered brain function couldn't cause the 'something in the blood' that affects cell function.

 

I'm not sure how you can know that, since it would be hard to tell when the virus starts replicating enough to trigger the immune system. Also, if it was triggered by the virus--or rather the immune system's response to the virus--that would be independent of exertion. I could certainly see how a viral infection might alter the body's response to exertion. The delay between exertion and PEM might involve several timed steps in the immune system response, and a virus might 'prime' some of those steps.

Life would probably be quite horrible if our immune systems reacted to all triggers with no delay at all. We must face lots of false triggers and brief triggers.

 

Why has no such specific location been revealed on the various brain scanning studies so far?

Of course localised could also mean peripheral.

How does the altered function (in a specific part of the brain) lead to "something in the blood"? It is easy to say "this could happen", much harder to devise strong testable hypotheses.

Cytokines/chemokines are secreted peripherally for specific reasons, so that cannot explain it. The primary function of neurotransmitters isn't "in the blood" (though elevated levels can spill over into the blood), and no unusual accumulation of any specific neurotransmitter has been found in the blood in adult patients.

A lack of elevated creatine kinase (post maximal CPET) also suggests symptoms are not due to muscle cells being damaged.