Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with CFS

sillysocks84

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I started taking this combo a couple of weeks ago:

250 mg CDP-choline
300 mg Pantethine
6 eggs daily (LOTS of choline in the form of phosphatidylcholine)
Also 1 g biotin, although I don't know if this has contributed to my success

My RHR has decreased from the mid 90s to the mid 70s. Also my HR seems less reactive and is less prone to suddenly swing.

I should start my own thread but I just wanted to chime in to say that in my case cholinergic supplements have helped my autonomic dysfunction.
How are your symptoms now? Did you or do you have other symptoms from your pots/oi? If so, did it help those as well?
 
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@Jonathan Edwards was this the EMERG meeting you attended today?
Yes, we discussed replicating the antibody findings. It is just a matter of logistics - the sort of logistics that the meeting was set up to capitalise on.

I have finally managed to look at the paper. The antibody findings look interesting but the difference between patients and controls does not make me think these are pathogenic antibodies actually causing symptoms. A proportion of controls had similar levels to patients -a smaller proportion, but not an order of magnitude smaller as far as I can see. This looks more like an indirect signal of some autoimmune process.
 

Marky90

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Yes, we discussed replicating the antibody findings. It is just a matter of logistics - the sort of logistics t
hat the meeting was set up to capitalise on.

I have finally managed to look at the paper. The antibody findings look interesting but the difference between patients and controls does not make me think these are pathogenic antibodies actually causing symptoms. A proportion of controls had similar levels to patients -a smaller proportion, but not an order of magnitude smaller as far as I can see. This looks more like an indirect signal of some autoimmune process.
Glad to hear you participate in these things professor,

Is there any interesting ideas in the researcher community when it comes to non-responders to Rituximab?
 

Hip

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Glad to hear you participate in these things professor
Prof Edwards is acting as the expert adviser for the setting up of the UK Invest in ME rituximab trials:
Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College London (UCL), has agreed to advise us on all aspects of the trial. He is known worldwide for his work in B cell immunology and as lead researcher in the clinical trials of Rituximab for rheumatoid arthritis. No UK expert is better placed than Professor Edwards to advise us on setting up a rituximab trial for ME patients.

You can read his statement on the trial here.


The antibody findings look interesting but the difference between patients and controls does not make me think these are pathogenic antibodies actually causing symptoms.
Would be technically possible to experimentally inoculate ME/CFS patients with recombinant muscarinic or recombinant adrenergic receptors, to act as a decoy antigens (sacrificial target antigens) for these autoantibodies?

Such decoy antigens should mop up the autoantibodies, and if these autoantibodies were driving ME/CFS symptoms, you might expect the symptoms to improve very soon after the decoy antigens are injected.

Might such a procedure help determine if these autoantibodies are functional or not?



What might elicit a response would be epitopes that have undergone post-translational modification during cell death. But since cell death is going on all the time in an active thymus this is a bit hard to predict.
Might then the triggering of autoimmunity arise from a normal cellular protein being cleaved by a viral protease, and then that protein escaping the cell during lysis?


And if so, if viral protease cleavage of cellular protein can in principle trigger autoimmunity, might this be where we could search for possible causal connections that link a specific viral infection to the specific autoantibodies found in the infected person?

Let me illustrate what I mean by an example: in the case of the muscarinic receptor autoantibodies found by Fluge and Mella, suppose we find that in a common ME/CFS-associated virus (like say enterovirus) there is a particular viral protease that is able to cleave the muscarinic receptor protein, and thus cause post-translational modification to this protein.

Let's say hypothetically we find that this viral protease is not able to cleave many other cellular proteins, but we observe it can cleave the muscarinic receptor.

So then we may start to think that this is more than a coincidence, and that the muscarinic autoantibodies found may be a direct result of the viral protease cleaving the muscarinic receptor protein.
 
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alex3619

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A fast but expensive way to demonstrate possible autoimmune problems is to filter the blood. There are machines that do that. I do not know the details with respect to antibodies though, nor the side effects. I believe costs are high.
 

MeSci

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Might then the triggering of autoimmunity arise from a normal cellular protein being cleaved by a viral protease, and then that protein escaping the cell during lysis?


And if so, if viral protease cleavage of cellular protein can in principle trigger autoimmunity, might this be where we could search for possible causal connections that link a specific viral infection to the specific autoantibodies found in the infected person?

Let me illustrate what I mean by an example: in the case of the muscarinic receptor autoantibodies found by Fluge and Mella, suppose we find that in a common ME/CFS-associated virus (like say enterovirus) there is a particular viral protease that is able to cleave the muscarinic receptor protein, and thus cause post-translational modification to this protein.

Let's say hypothetically we find that this viral protease is not able to cleave many other cellular proteins, but we observe it can cleave the muscarinic receptor.

So then we may start to think that this is more than a coincidence, and that the muscarinic autoantibodies found may be a direct result of the viral protease cleaving the muscarinic receptor protein.
Interesting idea, but why would it happen in some people and not others?
 

MeSci

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A fast but expensive way to demonstrate possible autoimmune problems is to filter the blood. There are machines that do that. I do not know the details with respect to antibodies though, nor the side effects. I believe costs are high.
You mean like dialysis?
 

user9876

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A fast but expensive way to demonstrate possible autoimmune problems is to filter the blood. There are machines that do that. I do not know the details with respect to antibodies though, nor the side effects. I believe costs are high.
I read about one similar machine where they filter out white blood cells then treat them with a drug and reinsert them. It was starting to be used with GVHD but had been tried on autoimmune diseases with some limited success. There are also machines that are used for filtering out different sections of blood for example granualcytes but I think they just remove some which are then transfused to patients with no immune system, I think the same machine is used for collecting what ever cells are necessary for a bone marrow transplant. In the UK the blood service operate these machines.
 

FancyMyBlood

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Probably not the best topic to post this, but because of this study the last 3 weeks I've been trying clenbuterol (a beta 2 agonist). Dosed up from 20 mcg to 120 mcg and I didn't notice a difference in ME/CFS symptoms.

Kinda makes sense since there are no reports of propanolol (beta 2 antagonist) doing anything in ME/CFS patients either.
 
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Yes, like dialysis, but there are other versions of the technology. I do not know all the details, its nothing I have investigated properly.
As halcyon says this is plasmapheresis. Some of the neurologists actually prefer it to rituximab for autoimmune problems because it works much quicker. It has been sued to remove autoantibodies in lupus for several decades. It is cumbersome and in the past quite dangerous - with a significant incidence of myocardial infarction. The biggest problem is that you need to keep repeating it indefinitely in a chronic autoimmune state and this is just impractical. The neurologists follow on with steroids and drugs like azathioprine. I would personally prefer to follow on with rituximab.
 
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Would be technically possible to experimentally inoculate ME/CFS patients with recombinant muscarinic or recombinant adrenergic receptors, to act as a decoy antigens (sacrificial target antigens) for these autoantibodies?

Such decoy antigens should mop up the autoantibodies, and if these autoantibodies were driving ME/CFS symptoms, you might expect the symptoms to improve very soon after the decoy antigens are injected.

Might such a procedure help determine if these autoantibodies are functional or not?
That sounds extremely impractical to me. Most receptors injected IV are likely to be taken up by savenger mechanisms and disappear immediately I think. there would also be the risk of feeding the fire of the B cell response to the antigen tenfold by presenting the antigen in a non-physiological way. Mopping up all the antibodies would require an awful lot of antigen and since antibody is constantly being produced you would have to do this on a regular basis. I can see that it might act as a diagnostic or mechanistic experiment as a one off but it sounds fraught with problems. If the decay was functional you might get dreadful vasomotor changes - like death for instance.

As indicated somewhere above, the difference in levels of antibodies between controls and patients in the recent study does not look to me to indicate that what is being measured is pathogenic. In the autoimmune diseases where we think antibodies are pathogenic the differences are much more clear cut.


Might then the triggering of autoimmunity arise from a normal cellular protein being cleaved by a viral protease, and then that protein escaping the cell during lysis?
And if so, if viral protease cleavage of cellular protein can in principle trigger autoimmunity, might this be where we could search for possible causal connections that link a specific viral infection to the specific autoantibodies found in the infected person?
I do not see why this should be a way to autoimmune disease. If antibodies are formed to the cleaved fragment that might be a good extra way to target the infected cells. Other cells would not suffer since they had no cleaved fragment on them. The body probably normally makes use of antibodies to degraded self material and these are not really within the definition of 'autoantibodies'. Antibodies to citrullinated peptides are maybe an exception, but citrullination is a normal degradation pathway which engages its own receptors and there are reasons for thinking it might cause generalised problems.

Let me illustrate what I mean by an example: in the case of the muscarinic receptor autoantibodies found by Fluge and Mella, suppose we find that in a common ME/CFS-associated virus (like say enterovirus) there is a particular viral protease that is able to cleave the muscarinic receptor protein, and thus cause post-translational modification to this protein.

Let's say hypothetically we find that this viral protease is not able to cleave many other cellular proteins, but we observe it can cleave the muscarinic receptor.

So then we may start to think that this is more than a coincidence, and that the muscarinic autoantibodies found may be a direct result of the viral protease cleaving the muscarinic receptor protein.
But if the antibodies are to a cleaved receptor they would not show up on an assay for the whole receptor. The antibodies that have been described are to whole receptor.
 

A.B.

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As indicated somewhere above, the difference in levels of antibodies between controls and patients in the recent study does not look to me to indicate that what is being measured is pathogenic. In the autoimmune diseases where we think antibodies are pathogenic the differences are much more clear cut.
So there must be some other undiscovered pathogenic antibodies?
 

Bob

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As indicated somewhere above, the difference in levels of antibodies between controls and patients in the recent study does not look to me to indicate that what is being measured is pathogenic. In the autoimmune diseases where we think antibodies are pathogenic the differences are much more clear cut.
I'm obviously not an expert but I can't help feeling that the observed changes (in levels of autoantibodies) are secondary to the main disease process i.e. knock-on effects. A useful starting point perhaps, in terms of identifying immune dysfunction, but I think we still need to look a lot deeper. I think we need to be careful to avoid giving undue importance to the first glimpses of abnormalities, as important as they are, so that we don't get stuck down blind ally ways. But that's not to downplay the importance of the research.
 
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Hip

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As indicated somewhere above, the difference in levels of antibodies between controls and patients in the recent study does not look to me to indicate that what is being measured is pathogenic. In the autoimmune diseases where we think antibodies are pathogenic the differences are much more clear cut.
I did see that, and that's why I was wondering whether there might be a way, like the decoy antigen idea, to empirically confirm that these autoantibodies detected by Fluge and Mella are not playing a causal role in ME/CFS.


Could another possibility be that these autoantibodies are not underpinning ME/CFS, but may be driving one or more of the comorbid conditions commonly found in ME/CFS?

Muscarinic and adrenergic receptor autoantibodies have been found in POTS and orthostatic hypotension (which are both listed as ME/CFS autonomic dysfunctions in the Canadian consensus criteria), and these autoantibodies have also been found in Sjogren's syndrome (which may be more common in ME/CFS 1).

If the autoantibodies that Fluge and Mella found are not underpinning ME/CFS, but rather causing POTS, orthostatic hypotension or Sjogren's, this could explain why these autoantibodies were not found in every ME/CFS patient — because not every patient has these conditions.

Here is a table of showing the various autoantibodies that different studies have found in ME/CFS, POTS, orthostatic hypotension and Sjogren's:

Code:
AUTO-ANTIBODIES FOUND IN ME/CFS AND ITS COMORBID CONDITIONS
——————————————————————————————————————————————————————————————————————————————
AUTO-ANTIBODIES                  ME/CFS     POTS     ORTHOSTATIC     SJOGREN'S
OBSERVED                                             HYPOTENSION     SYNDROME
——————————————————————————————————————————————————————————————————————————————
Adrenergic receptor alpha 1                  Yes
Adrenergic receptor alpha 2
Adrenergic receptor beta 1                   Yes         Yes
Adrenergic receptor beta 2         Yes       Yes         Yes

Muscarinic receptor M1             Yes       Yes
Muscarinic receptor M2                       Yes         Yes
Muscarinic receptor M3             Yes                   Yes            Yes
Muscarinic receptor M4             Yes

Dopamine D2 receptor               Yes
Mu-opioid receptor                 Yes
Serotonin 5-HT1A receptor          Yes
Serotonin (neurotransmitter)       Yes

Microtubule-associated protein 2   Yes
Phosphatidylinositol               Yes
Insoluble cellular antigens        Yes
Cardiolipin                        Yes
Heat shock protein HSP60           Yes
Anti-citrullinated protein         Yes
Note: Fluge and Mella's study found adrenergic beta 2, muscarinic M3 and muscarinic M4 autoantibodies in ME/CFS patients.

Refs: 1, 2, 3, 4, 5 6, 7, 8, 9, 10, 11

Another version of this table found here: autoantibodies in ME/CFS.


I do not see why this should be a way to autoimmune disease. If antibodies are formed to the cleaved fragment that might be a good extra way to target the infected cells. Other cells would not suffer since they had no cleaved fragment on them.
If I understood correctly, you hinted earlier that possibly an autoimmune response might be elicited from epitopes that have undergone post-translational modification during cell death.

So I wondered whether protein cleavage, which is a form of post-translational modification, could lead to an autoimmune response. Or is cleavage too large a modification, which too radically alters the protein? Perhaps you were thinking of more subtle forms of post-translational modification?[/URL]
 
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sillysocks84

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Muscarinic and adrenergic receptor autoantibodies have been found in POTS and orthostatic hypotension (which are both listed as ME/CFS autonomic dysfunctions in the Canadian consensus criteria), and these autoantibodies have also been found in Sjogren's syndrome (which may be more common in ME/CFS 1).
Yup. I've been talking with someone from dysautonomia international and they think ritux does best in pots and oi. So I'd say you hit the nail on the head there! Some of the side effects of rtx scares me, but dysautonomia international is looking at different things for the antibodies and I hope something less toxic than rtx!