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

[Jonathan Edwards]

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?

It just not seem to add up to me since the response would only be to the cleaved protein and that is not what is being measured. You would also need some form of T cell help to get the story off the ground. It all seems too speculative to be worth much brain power. Anything is possible but I think one has to have at least some reasonable leads.

 

[Hip]

Yup. I've been talking with someone from dysautonomia international and they think ritux does best in pots and oi.

Yes, I was thinking of starting a poll on that subject, to explore whether ME/CFS patients with one or more of these various autoimmune-linked comorbidities (POTS, orthostatic hypotension and Sjogren's syndrome) might be the best responders to rituximab.

@Rebecca2z seems to be responding very well to her rituximab treatment, and she said she has interstitial cystitis (IC), which is also found more commonly in ME/CFS.

It has been proposed that muscarinic M3 autoantibodies may be involved interstitial cystitis (although there has not yet been a study to confirm this). So we could tentatively add interstitial cystitis to the above table of ME/CFS comorbid conditions linked with adrenergic or muscarinic receptor autoantibodies.

So Rebecca's case supports this idea that those with these autoimmune-linked comorbid conditions respond best to rituximab.

But there have also been several people on this forum who did not respond to rituximab, so I'd like to start a poll to see whether or not they have these autoimmune-linked comorbidities.

 

[BurnA]

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.

Note: Fluge and Mella's study found adrenergic beta 2, muscarinic M3 and muscarinic M4 autoantibodies in ME/CFS patients.

However from what I remember, the data they had on patients with POTS, they didn't show elevated autoantibodies

You think you can join the dots sometimes but then there is a big hole in the middle.

 

[sillysocks84]

However from what I remember, the data they had on patients with POTS, they didn't show elevated autoantibodies

You think you can join the dots sometimes but then there is a big hole in the middle.

From an article dysautonomia international directed me to:

"POTS occurs frequently, but not exclusively, in younger females and its onset is occasionally preceded by or associated with a viral-like illness. It is more than a minor annoyance for most patients and leads to significant life changes and limitations in normal life. Our present study (Autoimmune Basis for Postural Tachycardia Syndrome) has produced data supporting the idea that production of autoantibodies, circulating proteins that normally fight such infections, have instead interacted with critical site(s) on specialized cell membrane proteins which alter their normal cell function.

These autoantibodies interfere with the system which controls the ability of blood vessels to constrict, which is needed to prevent a drop of blood pressure as a person stands. In POTS patients, this inadequate response to standing leads to a generalized increase of activity in the body’s sympathetic nerve system, which frequently normalizes the blood pressure. This increased nerve activity, however, increases the heart rate which is a prominent symptom in POTS.

We have also discovered a second group of autoantibodies in some POTS patients which directly increase the heart rate.

The combination of these two autoantibodies appears to cause the abnormal heart rate response observed in all 14 POTS patients we have tested to date for these autoantibodies. We have previously identified similar autoantibodies in individuals diagnosed with idiopathic orthostatic hypotension (Editor’s note: see Agnostic Autoantobodies as Vasodilators in Orthostatic Hypotension: A New Mechanism and Autoantibody Activation of Beta-Adrenergic and Muscarinic Receptors Contributes to an “Autoimmune” Orthostatic Hypotension).

These autoantibodies may explain why beta blockers aren’t always effective in treating the tachycardia seen in POTS, since beta blockers fail to completely block autoantibody activity on their protein receptor and they fail to alter the partial blockade of the autoantibodies on the arteriole blood vessels that initiate the orthostatic problem.

Confirmation of our findings will require testing a larger group of POTS patients for these autoantibodies. We hope to eventually develop treatments to block these autoantibodies, without blocking the target receptor proteins at the cell surface at the same time. Such agents are in development and within a few years may be applicable in POTS. This approach may prove useful in several other diseases which are caused by similar autoantibodies."

 

[alex3619]

The biggest problem is that you need to keep repeating it indefinitely in a chronic autoimmune state and this is just impractical.

I get that. However its a confirmation of autoimmunity. If it works, then an autoimmune problem is likely to be present, and so alternative therapies that are often also expensive and dangerous can be tried. What I do not know about is the relative risk profile. How common is an infarct for example?

 

[MeSci]

Don't we need to be looking at autoantibody levels that are significantly higher than in healthy controls? And are they?

 

[Jonathan Edwards]

I get that. However its a confirmation of autoimmunity. If it works, then an autoimmune problem is likely to be present, and so alternative therapies that are often also expensive and dangerous can be tried. What I do not know about is the relative risk profile. How common is an infarct for example?

The trouble is that the cost of doing a sham blinded study, which would be necessary, would probably be totally prohibitive. It is bad enough doing blinded controls for a couple of infusions. The costs lie in the administrative procedures needed.

Infarcts are probably now rare but thrombophlebitis is probably quite common. The replacement plasma is expensive. It also has the disadvantage that it does an 'oil exchange' on everything else in the blood as well so it is much more difficult to know what it means than rituximab.

 

[Jonathan Edwards]

Don't we need to be looking at autoantibody levels that are significantly higher than in healthy controls? And are they?

From what I can see of the recent data higher levels were more common in patients but the difference was one of numbers. A few normals had just as high levels. The situation for better understood autoimmune disease is not black and white either but it is more nearly so.

 

[alex3619]

Don't we need to be looking at autoantibody levels that are significantly higher than in healthy controls? And are they?

I am not sure this is right. That would be a crude indicator. Let us suppose for example that a patient has high levels of autoantibodies to a target that has little effect, due to low affinity or the specific epitope. Against that we have someone who has lower antibody levels but an epitope target that has high affinity, or a big gain in function, or a big loss of function.

Its not enough to know about antibody levels except as a crude indicator. You have to know what it is actually doing, and that might vary patient by patient.

In many cases its likely the key autoantibodies may not have been discovered yet. That is entirely possible. Its a long hard road to get the research done to find these antibodies.

 

[BurnA]

From an article dysautonomia international directed me to:
."

I know, this has been discussed ...
My point is that this study suggests autoantibodies present in POTS patients but of the patients in the recent paper none ( of the 4 ME patients they had data on) had elevated autoantibodies. Two of the non POTS patients did.
So where does that leave us ?

 

[Hip]

Yup. I've been talking with someone from dysautonomia international and they think ritux does best in pots and oi.

Does Dysautonomia International have a forum, by the way, similar to the www.dinet.org dysautonomia forums? And have there been many people there who have been treated with rituximab?

My point is that this study suggests autoantibodies present in POTS patients, but of the patients in the recent paper, none (of the 4 ME patients they had data on) had elevated autoantibodies. Two of the non POTS patients did.
So where does that leave us ?

Indeed, where does that leave us? Let's recap:

The 2014 study on 14 patients with POTS found that:
Beta 1 adrenergic receptor autoantibodies were present in all 14 POTS patients,
Beta 2 adrenergic receptor autoantibodies were present half of these patients.

So it looks like beta 1 adrenergic receptor autoantibodies are the most predictive of POTS.


Fluge and Mella's 2015 study looked for autoantibodies to all alpha and beta adrenergic receptor subtypes, but only found beta 2 adrenergic receptor autoantibodies.

So given that Fluge and Mella had four ME/CFS patients with POTS in their cohort, you would have expected that these researchers would find beta 1 adrenergic receptor autoantibodies in these patients, but they did not.

I don't know the answer to this conundrum.

 

[sillysocks84]

Does Dysautonomia International have a forum, by the way, similar to the www.dinet.org dysautonomia forums? And have there been many people there who have been treated with rituximab?

It looks like they do:http://forums.dinet.org/

I don't know if they have tried rtx or not. It seems like it's been alluded to that rtx is one of the agents they think could help, but nothing said out right about them knowing of anyone trying it. At least not in the email response I got. Try the forum link. I haven't been active there yet myself. Also they have other agents in mind besides rtx. So it is interesting.

 

[Hip]

@sillysocks84
That forum you posted is the Dysautonomia Information Network (DINET) forum.

The person you communicated with at Dysautonomia International who said that rituximab works best in cases of POTS or orthostatic intolerance: they must have known patients trying rituximab in order to make a statement like that.

 

[sillysocks84]

Oh oops! I guess I was confused about the forums then. I suggest emailing any rtx questions to this emailinfo@DysautonomiaInternational.org

The response I got was pretty fast. When I asked if rtx would work best in pots through b cell depletion, the response I got was "I think your question re rituximab hit the nail on the head". So I don't mean to suggest it would work best in pots over other cfs/me subsets. I reread that and I can see that is a misleading statement I apologize. Trying to keep up with my son while responding on here is not always smooth. Sorry!

 

[DeGenesis]

I see that beta-2 receptors are being mentioned a lot in the forum lately. I did a search of the forum (limited, I am dealing with ongoing eyestrain), but I can't find any information that indicates how beta-2 receptors might influence the disease (POTS or ME/CFS) in general. How would auto-antibodies to beta-2 receptors affect autonomic function. Also, if one wanted to test a hypothesis regarding beta-2 receptors, would low-dose propranolol be an option?

- Propranolol being a beta-1 antagonist and beta-2 antagonist
- Nebivolol being a beta-1 antagonist and a beta-2 agonist

Compare response?

 

[Hip]

How would auto-antibodies to beta-2 receptors affect autonomic function.

Autoantibodies to the adrenergic or muscarinic receptors found on autonomic nerves can attach to these receptors, and may then activate or block the receptor (autoantibodies can act as receptor agonists or antagonists). In either case, this messes with the autonomic nervous system, activating or blocking nerve signal transmission.

I was also recently reading this page of a book in which it says: "some functional autoantibodies do not produce a direct pharmacologic blockade, but instead inhibit the channel or receptor function by causing cross-linking and internalization of the target."

 

[halcyon]

How would auto-antibodies to beta-2 receptors affect autonomic function.

I think it becomes a bit more obvious when you look at the effects of activation of the beta-2 receptor, especially on tissues in the circulatory system:

• Heart muscle contraction
• Increase cardiac output (minor degree compared to β1).
  • Increase heart rate [11] in sinoatrial node (SA node) (chronotropic effect).
  • Increase atrial cardiac muscle contractility. (inotropic effect).
  • Increases contractility and automaticity[11] of ventricular cardiac muscle.
• Dilate hepatic artery.
• Dilate arterioles to skeletal muscle.

As Hip mentioned, these autoantibodies could either inappropriately activate these receptors or block normal activation, potentially disturbing normal function in either case.

 

[DeGenesis]

Thank you both for the summary. I appreciate it.

 

[Valentijn]

Isoprenaline sounds interesting: it's a B1 and B2 agonist which both raises systolic blood pressure and lowers diastolic blood pressure. It'd be interesting to see if those of us with narrow pulse pressure could get a normal pulse pressure from it.

 

[BurnA]

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.

Could you explain the reasoning for replicating the antibody findings? It seems like the consensus is that these findings don't necessarily point to anything specific so I am wondering if resources would be better spent elsewhere ? Or is there a thought that this is significant enough to warrent replication ?
Thanks.