A Unifying Hypothesis of the Pathophysiology of (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors: Wirth 2020

Sly Saint

Sly Saint

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A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
KlausWirtha CarmenScheibenbogen
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.

We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.

Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
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https://www.sciencedirect.com/science/article/abs/pii/S1568997220300823
(no sci-hub link yet)
 
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I was involved in a study with many years ago. Since I could not influence the results the technician explaned what was happening during the test. He dripped acetylcholine on my arm and then used a doppler machine to see how much the blood vessels opened and how long it took for the acetylcholine to be removed. Mine took much longer than found in healthy controls, and that was usual for ME.

It is the only test I have had done that showed something wrong!
 
This is so interesting. I hope this team of researchers (or others) will follow up with this with a really big sample size. So if it’s proved true we can possibly try to get medications that could work against these auto antibodies, or even symptomatic relief.

To me it certainly feels like problems with oxygen, circulation and vasoconstriction. I feel like there’s not enough oxygen getting to my brain - that’s the way I describe it to people. Isn’t that why sometimes meds for this, I forgot it’s name, are recommended for ME patients?
 
I don't understand this, but perhaps it has something to do with the fact that the two people in the family who happen to have pseudocholinesterase deficiency (meaning they do not have the enzyme to metabolize anesthetics to wake up afterwards) happen to have both gotten mono decades ago in high school and neither recovered from cfs. Or maybe there is no coincidence.
 
lunarainbows said:
This is so interesting. I hope this team of researchers (or others) will follow up with this with a really big sample size. So if it’s proved true we can possibly try to get medications that could work against these auto antibodies, or even symptomatic relief.
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Carmen Scheibenbogen has been looking at antibodies against beta-adrenergic and muscarinic cholinergic receptors in ME/CFS since at least 2016 (https://www.sciencedirect.com/science/article/pii/S0889159115300209). The results have been interesting. Charité Berlin is the biggest ME/CFS hub in Germany, possibly in Europe, and Scheibenbogen leads the EUROMENE working group on biomarkers for ME/CFS, so I hope she can push to get funding for a massive study.

Worth noting is Bhupesh Prusty's presentation at CMRC2020. When talking about the identification of the factor in the blood, he held back on presenting data about antibodies (17:45 in the recording, he mentions autoantibodies and antibodies against viruses). Given that he actively collaborates with Carmen Scheibenbogen, I am willing to bet they're looking into the autoantibodies mentioned in the article.

Lisa108 said:
The second author is well-known Prof. Dr. Carmen Scheibenbogen.

But the first author (Klaus Wirth) is a pharmacologist from Sanofi-Aventis, a pharmaceutical company... interesting....
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Klaus Wirth presented on "vascular dysfunctions in CFS" at the 1st Charité meeting on chronic fatigue in immune disorders (22 Nov 2019). Fatigatio briefly reported on his talk in their meeting notes (p. 12). Interesting to see someone from the R&D division of a major pharmaceutical lab working on ME/CFS, it might (might) mean they're onto a potential lead. The lack thereof meaning that there would be no financial incentive/justification for someone paid by Sanofi to spend time looking at ME/CFS.
 
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I guess that they had a so-so response previously by using immunoadsorption to remove ß2 adrenergic receptor antibodies. 3 out 10 patients had long lasting moderate to marked improvement for 6-12+ months. Maybe Sanofi has an interest in immunoadsorption?

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.

https://www.ncbi.nlm.nih.gov/pubmed/29543914
 
lunarainbows said:
This is so interesting. I hope this team of researchers (or others) will follow up with this with a really big sample size. So if it’s proved true we can possibly try to get medications that could work against these auto antibodies, or even symptomatic relief.
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I think we already have an adequate sample size. The problem for me is that the difference between ME and control was marginal - not the sort of difference that indicates any role in pathogenesis. Slightly up or down levels in antibodies are all over the place and are usually best ignored. The antibodies that we use diagnostically and think are pathogenically important show much more black and white differences.
 
Jonathan Edwards said:
I think we already have an adequate sample size. The problem for me is that the difference between ME and control was marginal - not the sort of difference that indicates any role in pathogenesis. Slightly up or down levels in antibodies are all over the place and are usually best ignored. The antibodies that we use diagnostically and think are pathogenically important show much more black and white differences.
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During the recent EUROMENE meeting Scheibenbogen said these antibodies belong to a group that play a role in regulating physiology. She thinks that ME/CFS is an illness where this regulatory system is not working correctly.

This is how I understood what she said at least and I might be remembering some details wrong.
 
I had 10 plasma exchanges and it did nothing. I have 2 friends who got immunoadsorption in Berlin. It did nothing. If you look into the study from Scheibenbogen in which she claims immunoadsorption helps, look at the step counter. It shows nearly the same numbers. I talked to one of the participants from this study. I did nothing for him besides claiming in the study. The study was coordinated with the
laboratory celltrend in luckenwalde. Who paid for everything and what a suprise is the only laboratory which lets you pay for testing those right now.
Not saying autoimmunity isnt at work in Cfs, but take those studies with a grain of salt.
 
strategist said:
During the recent EUROMENE meeting Scheibenbogen said these antibodies belong to a group that play a role in regulating physiology.
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I think she would like to persuade people of that but the data I have seen are very much against it.

lunarainbows said:
Is this the same acetylcholine that is related to myasthenia gravis? Or is that something else?
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The same acetylcholine but I think different receptors. Myasthenia affects the nicotinic receptors in skeletal muscle. I think the antibodies here are against the muscarinic receptors that occur in smooth muscle of blood vessels.
 
this article looks very interesting but it is largely too technical for me to understand - can anyone explain the key points to me in lay terms?

i am currently experiencing increasing cardiovascular symptoms and would like to understand more about the effects of ME on blood pressure control as most doctors are unaware of them - i'd like to know if this paper would clarify anything for them too
 
Stickyfingerstuff said:
this article looks very interesting but it is largely too technical for me to understand - can anyone explain the key points to me in lay terms?
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The basic idea is that for some people ME is an autoimmune disease where autoantibodies interfere with adrenaline binding to receptors, causing cardiovascular symptoms and that other people with ME have a similar cardiovascular problem but not due to antibodies.

There are two problems, though. Firstly, autoantibodies to adrenergic receptors are only very slightly higher in ME patients than healthy people - not the sort of difference that suggests that they matter. Secondly, if this really was a cardiovascular control problem then something consistent should be measurable in ME like a change in blood pressure or heart rate. And it should be a gross difference, not something requiring complicated tests. There is no such difference as far as we know.
 
Stickyfingerstuff said:
this article looks very interesting but it is largely too technical for me to understand - can anyone explain the key points to me in lay terms?

i am currently experiencing increasing cardiovascular symptoms and would like to understand more about the effects of ME on blood pressure control as most doctors are unaware of them - i'd like to know if this paper would clarify anything for them too
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May seem off topic but ---

Currently there is an application for (UK - MRC?) funding for a Genome wide association studies (GWAS) in ME. Check out @Simon M posts on the application i.e.on this site; there's also a proposal for a Norwegian GWAS study. If you Goggle something like "GWAS hypothesis free" then you'll see that GWAS studies, i.e. rather than saying something specific like "ME is autoimmune +----" - this study, look for gene associations which give a clue to the underlying cause.
 
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