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

[Valentijn]

The adrenergic alpha-2 receptor, if inactivated/rendered non-responsive to norepinephrine, could result in overproduction because the feedback mechanism for stopping its relase wouldn't work...

ADRA2A is over-expressed in ME patients following exertion, according to a couple publications by the Lights.

I have consistently low norepinephrine levels, based on 1 urine and 2 blood tests over the past 3-4 years. An NRI (Strattera) and a pretty specific ADRA2A/2B/2C antagonist (Yohimbine) help quite a bit with my low pulse pressure.

There are at least a few other patients on the forum who benefit from the same drugs, also in regards to their orthostatic intolerance. Could this situation also be explained in an autoimmune context?

 

[Gijs]

Valentijn, you have low boodpressure and low norepinephrine levels, this is the opposite of some other patiënts. So we can conclude that CFS/ME have at least two different groups: with over -and- underactivation of the autonomic nervoussystem and HPA-as. These groups must be split.

 

[Sidereal]

ADRA2A is over-expressed in ME patients following exertion, according to a couple publications by the Lights.

I have consistently low norepinephrine levels, based on 1 urine and 2 blood tests over the past 3-4 years. An NRI (Strattera) and a pretty specific ADRA2A/2B/2C antagonist (Yohimbine) help quite a bit with my low pulse pressure.

There are at least a few other patients on the forum who benefit from the same drugs, also in regards to their orthostatic intolerance. Could this situation also be explained in an autoimmune context?

I don't see any mention of them measuring antibodies to alpha 2 adrenergic receptor in this study. That's a pity because the Lights' work would suggest that this is an important piece of the puzzle. Not to mention the relatively recent paediatric study from Norway by Wyller who tried to show that CFS symptoms are due to chronic activation of the sympathetic nervous system (purportedly due to the catch-all explanation for everything - stress) but actually disproved his own hypothesis by showing that clonidine, an alpha 2 adrenergic autoreceptor agonist (in other words, a drug with sympatholytic properties), worsened functional outcomes compared to placebo, suggesting that the excessive sympathetic tone in the patients who do have it (not everyone does, some like Valentijn have the opposite problem) is probably a compensatory response by the body, perhaps existing to counter the effects of chronically depleted intravascular volume and/or abnormal regulation of vasoconstriction/vasodilation, perhaps due to some kind of an autoimmune process as suggested here.

 

[alex3619]

is probably a compensatory response by the body

This is a big issue. We have to be able to separate the effects of any antibody impact from effects of secondary compensation, from effects of any comorbid conditions including pathogens and nutrient depletion (e.g. CoQ10), and from genetic and environmental issues.

There are reasons I call it a big spaghetti tangle.

This is made more complicated by the issue that if the cell senses a problem it may overcompensate to cope. This often happens during some kind of demand. So the cell can go from one state to an extreme version of the opposite, at least temporarily.

I will say it again. ME may be one of the most complex diseases there is, and made even more complicated by interactions with "comorbid" diagnoses. I used scare quotes on "comorbid" because some of our comorbid problems might in some cases be really just a rarer symptom or consequence of ME.

It will take careful ongoing scientific investigation to tease out the pieces with any reliability.

 

[Gijs]

This is a big issue. We have to be able to separate the effects of any antibody impact from effects of secondary compensation, from effects of any comorbid conditions including pathogens and nutrient depletion (e.g. CoQ10), and from genetic and environmental issues.

There are reasons I call it a big spaghetti tangle.

This is made more complicated by the issue that if the cell senses a problem it may overcompensate to cope. This often happens during some kind of demand. So the cell can go from one state to an extreme version of the opposite, at least temporarily.

I will say it again. ME may be one of the most complex diseases there is, and made even more complicated by interactions with "comorbid" diagnoses. I used scare quotes on "comorbid" because some of our comorbid problems might in some cases be really just a rarer symptom or consequence of ME.

It will take careful ongoing scientific investigation to tease out the pieces with any reliability.

Yes Alex, and how can we know it is compensation? This is for me the one million dollar guestion. I think what Sidereal wrote is very plausible. Bloodflow/oxygen problems are the major key cause for our symptoms i think. So lets say it is a compensation reaction, why? We must try to answer this guestion. This is the route to find the disease mechanisme.

 

[MeSci]

Countrygirl prior to ME & during early years of illness my BP was normal/hypotensive.

In the ER I was given IV labetalol & clonidine lowering BP but not enough. So I was admitted to the cardio unit for further tests to rule out secondary causes of hypertension & to try other BP meds. I received excellent care & compassion from staff there. They're familiar with the condition, have tests & 60+ BP medications to work with.

When I searched the PR Cardiovascular Forum for" malignant hypertension" I didn't expect any hits. So when your post & those from @helen41, @Sidereal, @MeSci & others came up I was surprised & very grateful. Thanks again for posting.

Like MeSci's my pulse is now low, diastolic well controlled, & systolic more variable, sometime still high. I'm doing home BP monitoring.

We definitely need research focused on ME long-timers & the affect of normal cardiovascular physiologic changes over time on underlying conditions like POTS/NMH-- plus the B-cell association with hypertension.

My diastolic BP is sometimes high, notably when I have a migraine - a new problem that started last year. The low heart rate is due to my beta-blocker - nebivolol. Before my BP skyrocketed - discovered in 2005 - it was normal AFAIK, except when I was prescribed propranolol for anxiety, then I think it kept going very low judging by the fact that I kept going numb and almost blacking out. I had to stop taking it. I don't think I have OI, apart from the phenomenon of pounding pulse when I lie down, usually on my left side, which is variable. My heart rate doesn't seem to change when I stand up, which seems the commoner type of OI. I don't think my BP does either.

I so wish that the cause of my hypertension were properly identified and treated. When I asked my doc what he thought might have caused it in 2005, he said "The most common reason is no reason." Zero scientific curiosity (and precious little knowledge).

 

[Gijs]

My diastolic BP is sometimes high, notably when I have a migraine - a new problem that started last year. The low heart rate is due to my beta-blocker - nebivolol. Before my BP skyrocketed - discovered in 2005 - it was normal AFAIK, except when I was prescribed propranolol for anxiety, then I think it kept going very low judging by the fact that I kept going numb and almost blacking out. I had to stop taking it. I don't think I have OI, apart from the phenomenon of pounding pulse when I lie down, usually on my left side, which is variable. My heart rate doesn't seem to change when I stand up, which seems the commoner type of OI. I don't think my BP does either.

I so wish that the cause of my hypertension were properly identified and treated. When I asked my doc what he thought might have caused it in 2005, he said "The most common reason is no reason." Zero scientific curiosity (and precious little knowledge).

Your another case which shows us how different we are.. interessting: who of us do have Real ME in this topic? lol

 

[Valentijn]

I don't see any mention of them measuring antibodies to alpha 2 adrenergic receptor in this study. That's a pity because the Lights' work would suggest that this is an important piece of the puzzle.

Agreed. But it also might have a more direct impact, due to the way the adrenergic alpha receptors seem to interact with, oppose, and/or compensate for each other. Though it's been a while since I read about it much, and I don't think I understood it very well at the time.

 

[Valentijn]

My diastolic BP is sometimes high, notably when I have a migraine - a new problem that started last year.

If your diastolic rises while your systolic stays the same, your pulse pressure (the difference between the two) is narrowing. This can result in Neurally Mediated Hypotension or similar, if the pulse pressure is getting low enough. Normal is 40-50, and it feels pretty crappy when it's under 30. It can be delayed by quite a bit, sometimes not showing up until the end of the day, or after standing for a long time.

 

[Sidereal]

I don't think I have OI

How long were you standing still before measuring your BP and HR upright?

 

[alex3619]

"The most common reason is no reason."

There is always a reason. "No reason" is just shorthand for saying "I don't know but I do not want to admit ignorance". No known reason would be a better claim.

 

[MeSci]

If your diastolic rises while your systolic stays the same, your pulse pressure (the difference between the two) is narrowing. This can result in Neurally Mediated Hypotension or similar, if the pulse pressure is getting low enough. Normal is 40-50, and it feels pretty crappy when it's under 30. It can be delayed by quite a bit, sometimes not showing up until the end of the day, or after standing for a long time.

No - my systolic is high more often than my diastolic. I just mentioned that my diastole was sometimes high because @Gemini had just said "Like MeSci's my pulse is now low, diastolic well controlled, & systolic more variable, sometime still high." I wanted to correct a misconception. My pulse pressure is usually high, sometimes insanely so.

 

[MeSci]

How long were you standing still before measuring your BP and HR upright?

I don't know. How long should I wait for?

 

[Sidereal]

I don't know. How long should I wait for?

The time between standing up and changes in BP/HR and symptoms kicking in can vary quite a lot from patient to patient. For some people who have the TTT done it can take 30, 45 or even more minutes for their BP to crash. Neurally mediated hypotension, which is a common autonomic problem in ME/CFS, is a delayed phenomenon. It's not the same thing as orthostatic hypotension. Further complicating your situation is the fact that you have hypertension which could be masking your OI symptoms somewhat. You might have a situation where you feel fine until suddenly you start to crash and have to lie down immediately.

 

[MeSci]

The time between standing up and changes in BP/HR and symptoms kicking in can vary quite a lot from patient to patient. For some people who have the TTT done it can take 30, 45 or even more minutes for their BP to crash. Neurally mediated hypotension, which is a common autonomic problem in ME/CFS, is a delayed phenomenon. It's not the same thing as orthostatic hypotension. Further complicating your situation is the fact that you have hypertension which could be masking your OI symptoms somewhat. You might have a situation where you feel fine until suddenly you start to crash and have to lie down immediately.

I very rarely have to lie down - just sit down due to my legs being tired, or sometimes to walk on the spot as standing still also makes my legs tired. So would I have to stand still for up to 45 mins? Or could I be doing standing/walking activities? Activity usually increases my BP, I think.

 

[Sidereal]

I very rarely have to lie down - just sit down due to my legs being tired, or sometimes to walk on the spot as standing still also makes my legs tired. So would I have to stand still for up to 45 mins? Or could I be doing standing/walking activities? Activity usually increases my BP, I think.

I don't want to go too far off-topic but for the measurement to be valid it has to be standing still, no moving or even fidgeting. I was surprised by how hard it was the first time I tried it. Only lasted a few minutes before getting woozy. I wouldn't recommend doing this alone because the suddenness of the reaction may take you by surprise and you could have a syncopal episode or just get unsteady and fall and injure yourself before you've had a chance to sit/lie down.

 

[voner]

I thought this statement in the paper was also significant (I added the bolding for emphasis) :

Our observation of a decrease of M and ß receptor autoantibodies in patients responding to rituximab, in whom levels pre-treatment were within the normal range of control subjects, suggests that we may miss functionally pathogenic antibodies by just assessing quantitative levels by ELISA.

 

[nandixon]

I don't see any mention of them measuring antibodies to alpha 2 adrenergic receptor in this study. That's a pity because the Lights' work would suggest that this is an important piece of the puzzle.

If we're lucky, they might have looked at the alpha-2 adrenergic receptor (α2 AdR) after all. In the Results section of the paper it's stated:

Analysis of patient and control samples for antibodies against α adrenergic, dopamine receptors D1, D2S, D3, D4.2, D4.4 and D4.7 and serotonin receptors 5HT1A, 5HT2A, 5HT2B, 5HT2C, 5HT5A, 5HT6, 5HT7 as well as the endothelin (ET) and angiotensin receptor (AT) did not reveal immunoreactivity neither in patient nor control cohort. Fig. 1D shows data for AT, ET, D1, 5HT1A, and α1 AdR.

So in Fig. 1D they're providing one representative example from each of five receptor categories. In theory, the "α adrenergic" receptor category, as they've broadly stated it, should include both alpha-1 and alpha-2. So there's at least a chance they could have tested for both, but just selected the α1 AdR as the one representative example from that category for purposes of Fig. 1D, and omitted mentioning α2 AdR.(?)

So they may have found no significant autoantibodies with respect to the α2 AdR. I guess we'd need to contact the authors to check on this.

(Agree about the Lights' work - their whole series of papers are important, I think.)

 

[Sidereal]

So in Fig. 1D they're providing one representative example from each of five receptor categories. In theory, the "α adrenergic" receptor category, as they've broadly stated it, should include both alpha-1 and alpha-2. So there's at least a chance they could have tested for both, but just selected the α1 AdR as the one representative example from that category for purposes of Fig. 1D, and omitted mentioning α2 AdR.(?)

So they may have found no significant autoantibodies with respect to the α2 AdR. I guess we'd need to contact the authors to check on this.

Yes, I did see that, but because the Figure was labelled "alpha 1" I assumed they only measured that one. Alpha 2 is not mentioned anywhere explicitly (that I can see). It would be good to get some clarification on this from the authors because it would seem like an important thing to measure given the existing papers by the Lights.

 

[Sasha]

I don't see any mention of them measuring antibodies to alpha 2 adrenergic receptor in this study. That's a pity because the Lights' work would suggest that this is an important piece of the puzzle.

All this discussion is over my head but Alan Light is giving a Solve webinar in a couple of weeks - would it be helpful to email him with any relevant questions before the talk?