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

[jimells]

I realize that this research is exciting for us but not so much for the public, or maybe even medicine in general. Still, it's a little disheartening that the media has so far completely ignored these findings. At least, I haven't been able to find any news stories yet.

Has anybody here seen anything in the media?

 

[adreno]

I also wondered what might happen downstream of this downregulation of receptors, for example might there be a chronic upregulation of sympathetic tone as an attempt to compensate for the appropriate signals not getting through to receptors?

Yes, this is very likely.

 

[alex3619]

Has anybody here seen anything in the media?

I think these findings would be considered trivial by the general media. It does not lead to a cure, or test. It might lead to major discoveries, particularly if the antibodies are found to cause damage. "Might" does not grab headlines. Media do not just publish things because they are of scientific interest.

Now I suspect this may be written up in various scientific magazines etc. That is where we might be looking in the media.

 

[alex3619]

I also wondered what might happen downstream of this downregulation of receptors, for example might there be a chronic upregulation of sympathetic tone as an attempt to compensate for the appropriate signals not getting through to receptors?

To add to what @adreno said, I think its more than just likely. These receptors and their function are under considerable regulation and control, and interaction with other factors. Other things going in ME might also impact this. Its a very complex situation, and I do not expect we will fully understand it all in my lifetime. However we don't need to, just to understand enough to lead us to treatments and cures. Type 2 diabetes is not fully understood either, but its treatable.

 

[sdmcvicar]

The nice thing about this finding (for me, an analytical biochemist) is that it's very amenable to retest in a research environment. As stated in the 9 pages of comments (Wow, hot topic!), it depends on whether these antibodies are agonistic or antagonistic. Very interesting result for the proponents of "adrenal fatigue" and HPA axis dysfunction as a subgroup!

It also sets up for screening of patient samples to verify a defined subtype. Something like the ciraplex assay might be useful for this. Instead of covering a well with a single antibody as is done in ELISA, up to 12 immunospots are printed in a ring around the well. This would allow researchers to look at all of the autoantibodies that had a positive correlation with CFS, and determine if relative levels of several autoantibodies predict symptom severity.

Generating DNA aptamers to the autoantibodies from specific strong responders to rituximab could also be interesting, as they can be made rapidly and could distinguish between the different binding regions where the autoantibodies attach to on a single receptor.

That's fantastic. Can't happen soon enough.

In fact, how long would a study like that take to do? Do we already have some well-defined cohorts kicking about?

As for defined cohorts of patient samples, this looks like a perfect opportunity for incorporation into both the Open Medicine Foundation's severely ill-big data research project, and their broader aim of generating internet and app-based tools for reporting by patients and patient advocates. The SolveCFS BioBank would be another potential route for donation of samples. Strong follow-up research might give them the ammo they need to get funding for a full-time repository, rather than having to be on-demand as specific protocols get approved. I see that as the big barrier to quick retesting. A 3-month lead time would probably be enough to generate an appropriate screening assay, and a month would be plenty of time to run patient samples in the thousands, but grant approval, protocol approval, patient enrollment and curation of patient clinical data for each sample would likely add two years as an optimistic estimate.



Sorry for the scattershot of ideas folks, it's a rough day.

 

[Gijs]

@sdmcvicar, you wrote:''it depends on whether these antibodies are agonistic or antagonistic''. Isn't autoimmunity not always antagonistic when it attack receptors? I don't understand it.

 

[A.B.]

The nice thing about this finding (for me, an analytical biochemist) is that it's very amenable to retest in a research environment. As stated in the 9 pages of comments (Wow, hot topic!), it depends on whether these antibodies are agonistic or antagonistic. Very interesting result for the proponents of "adrenal fatigue" and HPA axis dysfunction as a subgroup!

"functional" hypoglycemia and low cortisol? In a certain sense these are indeed functional, but these receptor antibodies provide a biological explanation alternative to childhod trauma and somatization of depression.

 

[Research 1st]

Lets be realistic.

Autoimmune autonomic neuropathy (ME) research won't get far in the UK in it's present form of who rules the roost (MRC) . They fund CFS psychiatry and more recently some small scale biological fatigue work as equating to ME).
In the states there is the CDC. Won't even bother discussing their track record, considering they created CFS in he first place.

With such paucity of funding by NATO countries who know the cause, you can't convince people at all to get onboard the autoimmune brain disease train, when disinfo is 'evidence based', and utilises the pacifier of social psychiatry.

Due to the CDC creating CFS, and the British tagging CFS onto ME. ME is misrepresented via CFS/ME,which is unexplained long term tiredness, PEM and one symptom. (Thus not ME).

So the majority of GP diagnosed CFS or ME patients in clinical practice, (people then who become part of research studies) are simple Chronic Fatigue cases (as this research shows, and as we knew anyway). No CFS or CFS/ME or ME research results can be consistent unless they are selected as 'well defined' patients. Criterias help his, but don't guarantee it. (When patients sue their respective governments for wilful neglect in the future, this will all come to light, and it was all avoidable). ME could have stayed ME, but the CDC and others had other ideas.

Could novel autoimmunity directly link to ME? Yes, but autoimmunity is not the cause, but one effect of ME. The cause is the the immunosupressive agent. (Spirochette, Retrovirus etc) allowing countless other infections to take hold, infections people on this forum find over and over again, but Dr Lipkin says he can't find any - probably as his blood samples aren't from people with ME, but Chronic Fatigue! Genuine, organic CFS and ME patients are riddled with infections if you don't just look at antibodies (once the blood cells are infected in Lyme, there is no immune response, so you need PCR and even then that would show tissue infection), These are the same infections found in AIDS and 'Chronic Lyme disease', aka AIDS V2.0 which is probably nothing to do with Lyme anyway (Borrelia just being present due to the other immuno suppressive agent) and is actually ME.

As these immune suppressed patients are rarely studied (outside of Dr's - De Meirleir, Peterson & Montoya) and the neuropsych model of moderate affected CFS with no inflammation is preferred politically. With such control over what 'ME' is (anything but ME actually) then our friend Dr Edwards or anyone else cannot possibly influence the state position on ME denial, as there is no funding anyway for ME to 'prove' an autoimmune theory of ME when mixed cohorts are analysed.

We have no funding. The Americans spend less on CFS, than Hayfever, despite Lyme, never mind CFS, (affecting 10X more people than HIV).

This designed neglect of ME denial, means UK patients themselves, and their supporters end up funding the UK Rituximab trial idea . Conversely, ME denial (BPS CFS) continues to be funded by the MRC who Dr Shepherd sits on an MRC panel with. No progress there for severe ME though.. Dr Shepherd has been pulling his hair out from day one, to get ME seen as neurological (and nothing ever changes. No one listens to him, as the people he has to tolerate, deny ME exists away from 'Chronic Fatigue'. So what can he do? Just keep plodding on, over multiple decades, that one day, the people with power retire and go away and new people can influence the grant applications for serious biomedical research to not be rejected (The MRC have rejected biomedical research applications, but do accept BPS theory CFS, that isn't even science but religion). Nice.

Without the pathogen studies being published yet, autoimmunity proves nothing politically that ME is a transmittable to family members, neuroinvasive immuosupressive agent. In time, that will be demonstrated in some. Meanwhile, autoimmunity findings won't change much to the sceptical dumbo ears that won't listen to 5,000 biomedical papers on CFS. (This is more to do with human stupidly and arrogance than just CFS ME controversy).

Politics ruins lives, as well as those chronically ill, censored by politics and models of cost effectiveness and political correctness. Some Multiple Sclerosis (MS) (MS can cause paralysis and death) patients have pathogenic HERV activity (activated endogenous retroviruses)

Without the pathogen studies in ME organic CFS, it's plausible denial all the way until then, and appeals to authority. When XMRV nonsense was around, Wessely hilariously stated in the press that even if a retrovirus caused CFS, it ''doesn't explain childhood trauma''. This is the mindset of ME always equals F48.0 CFS, you cannot alter their beliefs - unless you utilise CBT whilst reading psychiatric theories to see if they still work after analysis. With CBT, they work are cost effective, and safe for all.

For severe ME in the UK, we have to see autoimmune treatment fail in these same patients, for severe ME to recognised: The good news is, Rituximab looks like it doesn't work for the long term severely affected. This, ironically, will expose severe chronic ME, as researchers will find out why having ME for 30 years ruins your immune system and the damage it causes that cannot be fixed with a B Cell depletion therapy to recover 100% former health.

Then the penny will drop.

Chronic disease doesn't work like that and autoimmune diseases kills people and causes so many things to go wrong from heart failure, cancer, neuralgia's, arthritis etc. The most sick patients will be up in arms their 'fellow Americans' with moderate CFS are back at work, and they remain bedridden or house bound as they're well past autoimmunity and into the realms of endothelial damage heart attacks and strokes from oxidised plaque (from uncontrolled oxidative stress). This is predictable. Hence the UK state won't fund the Rituximab trial (Invest in ME does - a charity), and there is nothing any of can do about it unless you crowd fund biomedical research studies, as patients, yourselves.

There is a catch 22: You need scientific evidence to get people on your side to further autoimmune/inflammatory brain research, and to get people on your side, you need the funding to garner scientific attention, that isn't given because it hasn't been done yet.

 

[alex3619]

@sdmcvicar, you wrote:''it depends on whether these antibodies are agonistic or antagonistic''. Isn't autoimmunity not always antagonistic when it attack receptors? I don't understand it.

Not necessarily. Typically antibody attack means loss of function. Antagonistic means loss of function, or reduction in function. However it could also induce gain of function. That would result in it being agonistic. I think agonistic is probably much less common, but it does exist.

Validating the antibody findings is only part of the problem. It would be nice to know what epitopes they bind to. How they affect receptor function. If this could be considered irrelevant, contributing, or causal. So many questions. This is the start of a research road, or at least a next step after testing Rituximab.

 

[Marco]

@sdmcvicar, you wrote:''it depends on whether these antibodies are agonistic or antagonistic''. Isn't autoimmunity not always antagonistic when it attack receptors? I don't understand it.

Easy to find the concept intuitively hard to grasp. As I understand it 'anti' in antibodies is the same as anti in 'antichrist'. At least in strict theological terms (as opposed to in popular fiction) anti suggests something that takes the place of something else rather than always antagonises it. Autoantibodies may 'take the place' of native actors on receptors. The effect they have, agonistic, antagonistic, neutral and and degrees in between may depend on such things as the particular 3D structure of the receptor at the time.

 

[sdmcvicar]

Easy to find the concept intuitively hard to grasp. As I understand it 'anti' in antibodies is the same as anti in 'antichrist'. At least in strict theological terms (as opposed to in popular fiction) anti suggests something that takes the place of something else rather than always antagonises it. Autoantibodies may 'take the place' of native actors on receptors. The effect they have, agonistic, antagonistic, neutral and and degrees in between may depend on such things as the particular 3D structure of the receptor at the time.

So, for example, if the adrenergic B2 antibody is a receptor agonist, the receptor is activated, just as if it had received its natural chemical signal. If the autoantibody is a receptor antagonist, then it is positioned at a different place on the receptor molecule and prevents natural chemical signals from activating it. There are still other places where an autoantibody might bind, causing the receptor to be more or less strongly activated.

To put this in the context of a patient's perspective, an autoantibody agonist would increase vasoconstriction in the short term. Over time, constant activation of the receptor might cause the cells to reduce or eliminate the amount of receptors they produce, so that they are no longer being constantly activated by an erroneous signal. This might explain those burst of energy/crash cycles patients experience in the near term, as the body responds to an essentially heightened state of epinephrine (aka adrenaline), then has to recover its resources. After a couple years of this, the body may have modified itself to a point where it doesn't even mount a normal adrenal response, which could lead to POTS/OI (because the normal vasoconstriction that maintains blood pressure going from sitting to standing doesn't occur), or the inability to repeat exercise at the same level two days in a row (because the biochemical response counters what it thinks to be a flare in autoantibody production).

This is part of why medical research is so hard... many hypotheses can fit the same set of symptoms, and the human body is constantly modifying itself to maintain an equilibrium as best it can!

 

[MeSci]

There is an antibody induced hypertension I think . I have never investigated it. I have no idea about what changes in treatment choices this would mean, this might be in existing published literature.

I also have high BP, but with severe NMH. The BP partially compensates for orthostatic crashes.

PS eg http://www.hindawi.com/journals/bmri/2014/504045/

I see that paper refers to molecular mimicry as a possible mechanism, which @Jonathan Edwards would probably not agree with.

It's so refreshing to read about theories for the bases of hypertension, as opposed to doctors' habits of just throwing one or more of the standard antihypertensive drugs at it.

 

[sdmcvicar]

One other nice thing: even preliminary validation of an antibody correlation could be used to help define a cohort for clinical trials of Rituximab, or identify a "responder" phenotype in post-hoc analysis. It's the dream of personalized medicine.

Validating the antibody findings is only part of the problem. It would be nice to know what epitopes they bind to. How they affect receptor function.

If I were healthy enough to lead a project, these are exactly the kind of questions I'd be looking to answer with a grant proposal.

This whole thing takes me back to the Suhadolnik "low molecular weight RNAse L" discovery days. Each answer brings 10 new questions.

[edited for clarity, and to remove evidence of mixed tenses]

 

[Gijs]

Thx, Alex, Marco and sdmcvicar.... i understand it a little better now.

 

[Gijs]

sdmcvicar, which receptor(s) could lead to an overactive production of (nor)adrenaline?

 

[Marco]

So, for example, if the adrenergic B2 antibody is a receptor agonist, the receptor is activated, just as if it had received its natural chemical signal. If the autoantibody is a receptor antagonist, then it is positioned at a different place on the receptor molecule and prevents natural chemical signals from activating it. There are still other places where an autoantibody might bind, causing the receptor to be more or less strongly activated.

To put this in the context of a patient's perspective, an autoantibody agonist would increase vasoconstriction in the short term. Over time, constant activation of the receptor might cause the cells to reduce or eliminate the amount of receptors they produce, so that they are no longer being constantly activated by an erroneous signal. This might explain those burst of energy/crash cycles patients experience in the near term, as the body responds to an essentially heightened state of epinephrine (aka adrenaline), then has to recover its resources. After a couple years of this, the body may have modified itself to a point where it doesn't even mount a normal adrenal response, which could lead to POTS/OI (because the normal vasoconstriction that maintains blood pressure going from sitting to standing doesn't occur), or the inability to repeat exercise at the same level two days in a row (because the biochemical response counters what it thinks to be a flare in autoantibody production).

This is part of why medical research is so hard... many hypotheses can fit the same set of symptoms, and the human body is constantly modifying itself to maintain an equilibrium as best it can!

Yep all those things are possible including 'paradoxical' effects which makes it so tough to work out what is happening in a multisystem disorder.

 

[anciendaze]

On antibodies and agonists: there is actually an analogy with a very widely-known means of modifying activity at synapses used in SSRI antidepressants. By blocking reuptake of the neurotransmitter you allow the molecule to bounce around the synaptic cleft so that the same molecule binds to the receptor many times. There is also the problem of releasing the molecule from the receptor. Forming a permanent bond is like destroying the receptor, but releasing the molecule too easily can allow it to be counted repeatedly. The linkage between the receptor and biological activity can be quite complex, for example in gated ion channels, where it is the flow of ions which determines strength of response. Finally, there are protein-linked receptors where we simply don't know what is going on in sufficient detail. Other experience with proteins tells us they can have a very wide variety of behaviors, which can change markedly as the protein changes shape. (If it were easy to predict the way proteins fold, there wouldn't be a Folding@home project.) This research explicitly dealt with G-protein-linked receptors.

Immune signalling involving peptides and proteins is still partly terra incognita. Discoveries about the role of PEPITEM in recruitment of cytotoxic T-cells to inflamed tissues were only published this year.

 

[sdmcvicar]

sdmcvicar, which receptor(s) could lead to an overactive production of (nor)adrenaline?

Oh god, not really qualified to answer this one. Neurochemistry is not my strong suit. Also, the question is very broad, like asking what receptors are involved in epilepsy. Anyone else with a better answer, shout out to add/modify:

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...

Any of the adrenergic receptors, including alpha, beta-1, beta-3, as if their function is impaired, norepinephrine and epinephrine production might be increased to compensate.

Absolutely anything that activates the sympathetic nervous system... eg. cytokine receptors (IL-1R, TNFR1, TNFR2)

Even any neurotransmitter reuptake transporters.

However, this doesn't even need to be receptor-mediated. Any lesions affecting the sympathetic or parasympathetic nervous systems could cause norepinephrine overproduction.

 

[adreno]

Oh god, not really qualified to answer this one. Neurochemistry is not my strong suit.

I think you did pretty well

 

[Snow Leopard]

So, for example, if the adrenergic B2 antibody is a receptor agonist, the receptor is activated, just as if it had received its natural chemical signal. If the autoantibody is a receptor antagonist, then it is positioned at a different place on the receptor molecule and prevents natural chemical signals from activating it. There are still other places where an autoantibody might bind, causing the receptor to be more or less strongly activated.

There are several types of agonist:

Full agonist (similar signal to a strong natural ligand).

Partial agonist. These can act as competitive antagonists and limit the magnitude of the overall signal (since less receptors will become activated).

Inverse agonist (that not only blocks the receptor from functioning, but causes negative feeback).

There are several types of antagonists:

Competitive antagonists (where the total number of binding sites are limited). It is competitive in the sense that it requires a much higher concentration of the natural ligands to overcome the antagonist. A typical biological system (which has some feedback systems) will try to up-regulate the (natural ligands) if possible.

Non-competitive antagonists. In this case, it really doesn't matter how much of the natural ligand there is, the signal will be limited. These can either bind to the active site, or another site, which either causes conformational changes in the receptor to prevent binding at the active site, or prevents conformational changes required for activation when the natural ligand binds. Either way they block the receptor from being activated.

Uncompetitive antagonist. These only bind once the receptor is already activated, and therefore does not limit the signal completely, but limits the magnitude of the signal.

But it is not merely where the ligand binds, but also the receptor-ligand binding kinetics that matters. Ligands, including antibodiesnot only have different binding affinities but also have different kinetics and in turn, different signalling rates and magnitudes. The resulting kinetics strongly determine the effects of competitive antagonists and partial agonists, for example.

Anyway, all this means is that the downstream pathways that these receptors normally activate need to be measured in patients before we can start to understand whether these autoantibodies have any pathological effects.

Generating DNA aptamers to the autoantibodies from specific strong responders to rituximab could also be interesting, as they can be made rapidly and could distinguish between the different binding regions where the autoantibodies attach to on a single receptor.

How exactly would you identify the relevant binding regions? I mean in a typical aptamer experiment, the aptamers would stick anywhere they felt like (okay, based on stochastic effects) on the target ligand. Unless you add some steps where you bind something else to the antibodies to block the aptamers from sticking to the wrong places and filter them out. But if you knew where the 'wrong places' were, then why would you be doing the experiment in the first place?