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

[Gijs]

Good idea.

Solve also lists two research studies underway at Missouri & Harvard involving antibodies/autoantibodies:

http://solvecfs.org/research/cfidsaa-research-program-for-researchers/michael-cooperstock-m-d/

http://solvecfs.org/research/cfidsaa-research-program-for-researchers/steve-elledge/

Perhaps someone at Solve can give us a status report & ask Cooperman/Elledge--
(1)what their assessment is of this discovery
(2)whether they can include these autoantibodies in their on-going studies?

Great news! I think there are more antibody studies needed. There findings will be different in each patiënt. If you have elevated antibodies and it fits with your symptoms you definetily have an autoimmuneproblem primary or secondary. But this is not the whole story for all ME patiënts. We have also allergic reactions (against food), reactivation of EBV etc... something must be going wrong with our immune system.

 

[sillysocks84]

@Gijs

one of the antibodies, that was elevated in patients and that fell with rituximab treatment, was to the β2 adrenergic receptor, which is involved in inhibiting histamine release from mast cells.

https://en.wikipedia.org/wiki/Beta-2_adrenergic_receptor

I have food intolerance and allergic reactions, so I think what they have found so far is promising in helping that.

 

[Gijs]

@Gijs


I have food intolerance and allergic reactions, so I think what they have found so far is promising in helping that.

This finding against beta-2 receptor is consistent in POTS patiënts too but there are more.

 

[sillysocks84]

This finding against beta-2 receptor is consistent in POTS patiënts too but there are more.

B2 recept is responsible for many other complications we have or acqire. I just wonder when we all can be offered this treatment? And if we can try it now, since ours is rare. Or considered rare enough that we all have been put on the back burner too long.

 

[anciendaze]

@anciendaze, B cell clonal expansion has been anecdotally noted by researchers in ME/CFS several times.

So has an association with rare leukemia/lymphoma, not that you will find this in published official material. Considering my limited range of contacts, due to illness, it can't be very likely that I would know of such a case among people met before I knew anything about this disease. I have since learned of similar cases among people encountered after I began to investigate this disease. Either this is an extraordinary fluke or the association is much higher among patients than officially assumed. We are talking about at least an order of magnitude, and quite possibly two orders of magnitude. Ignoring this is like ignoring the association between asbestos and mesothelioma.

 

[Gemini]

Do we already have some well-defined cohorts kicking about?

Perhaps ask Drs. Lipkin/Horning about theirs & if Columbia would study these autoantibodies.

He noted polyclonal hypergammaglobulemia was the one consistent finding in his current & past ME/CFS research.

From Cort's recent post: "Dr. Horning proposed that an autoimmune process may be fueling the symptoms in a subset of patients" (Mady Horinig: Tea-Time at Simmaron)

 

[Marco]

In ME a triggering event that impacts the immune system seems to start it all off. Then, again presuming the antibody findings are very important and even causative, autoantibodies start targeting tissues and doing damage. However that damage would accumulate, and how the body adapts to that damage will change over time. Its not static damage either, its continuing damage and repair, in a kind of not-so-cold-war.

Ah - but who's to say that autoantibodies have to be destructive. Isn't it possible that they might affect signalling at receptors/regulation of ion channels without causing physical damage. To paraphrase the physicist/author Carlo Rovelli - sometimes it's better to ask the question 'why not'?

 

[Marco]

From http://www.dysautonomiainternational.org/blog/wordpress/new-evidence-of-autoimmunity-in-pots/
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.

Can anyone shed more light on this ?

I posted a link to review paper earlier in this thread that suggested various approaches which may or may not be feasible in the medium term. For example :

Two approaches have been established to neutralise β1AR autoantibodies by the systemic application of ligands that mimic the targeted epitope. One type of such synthetic neutralising ligands has been made by affinity selection and single step exponential enrichment of a short single-stranded nucleotide sequence (aptamere) [73] that binds with high affinity to the epitope recognition site of β1AR autoantibodies.

The other approach consists in a peptide-based strategy aiming to specifically neutralise conformational β1AR autoantibodies directly in the circulating blood to prevent their harmful cardio-stimulatory effects.

More detail if you're interested :

http://www.sciencedirect.com/science/article/pii/S1568997214001657

 

[alex3619]

Ah - but who's to say that autoantibodies have to be destructive. Isn't it possible that they might affect signalling at receptors/regulation of ion channels without causing physical damage. To paraphrase the physicist/author Carlo Rovelli - sometimes it's better to ask the question 'why not'?

Which does damage. Indeed it has been proposed that electromagnetic sensitivity is due to impact on voltage gated ion channels. Anything that disturbs the regulatory processes will probably do damage, its just that it might be more subtle than what we might see otherwise. I am not presuming damage is direct tissue damage, especially not if the target is a neuro- or hormone-receptor.

 

[Hip]

Two questions I have about this Fluge and Mella paper; in the paper it says that:

29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors [these receptors being the ß2, M3 and M4 receptors].

Elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.

Since Fluge and Mella observed this reduction in autoantibodies in patients who responded to rituximab, does this mean that in this study, Fluge and Mella only treated patients initially exhibiting autoantibodies (ie, only treated the 29.5% of patients who were initially found to have elevated autoantibodies)?

Or did they also give the rituximab treatment to ME/CFS patients who did not exhibit autoantibodies? If so, did any of these patients without autoantibodies respond to rituximab? Or is having ß2, M3 or M4 autoantibodies a necessary (but not sufficient) condition for treatment success with rituximab?

 

[Marco]

Which does damage. Indeed it has been proposed that electromagnetic sensitivity is due to impact on voltage gated ion channels. Anything that disturbs the regulatory processes will probably do damage, its just that it might be more subtle than what we might see otherwise. I am not presuming damage is direct tissue damage, especially not if the target is a neuro- or hormone-receptor.

Subtle or no existent. I read one paper recently that suggested that autoimmunity in some types of neuropathic pain produces NO physical damage at all although if it produces microglial activation then there may be downstream damage from elevated PIC's; oxidative stress; extracelullar glutamate toxicity etc - but this is quite a different scenario from the usual autoimmune inflammatory tissue damage.

 

[Snow Leopard]

Since Fluge and Mella observed this reduction in autoantibodies in patients who responded to rituximab, does this mean that in this study, Fluge and Mella only treated patients initially exhibiting autoantibodies (ie, only treated the 29.5% of patients who were initially found to have elevated autoantibodies)?

Or did they also give the rituximab treatment to ME/CFS patients who did not exhibit autoantibodies? If so, did any of these patients without autoantibodies respond to rituximab? Or is having ß2, M3 or M4 autoantibodies a necessary (but not sufficient) condition for treatment success with rituximab?

The answer is in these graphs posted by Sidereal:

http://forums.phoenixrising.me/inde...in-patients-with-cfs.40109/page-2#post-644120

Reduction of the autoantibodies was associated with improvement in some patients. Yet some patients responded without those particular antibody levels dropping and some failed to improve and antibody levels did not drop, others had low levels of those particular antibodies, so no notable drop was possible, yet were also responders to the drug.

In my opinion, this suggests that this finding is secondary to other immune dysregulation, possibly driven by an autoimmune disease with as yet unknown targets.

 

[anciendaze]

...In my opinion, this suggests that this finding is secondary to other immune dysregulation, possibly driven by an autoimmune disease with as yet unknown targets.

I fully agree with your conclusion, but I feel it necessary to emphasize that immune dysregulation is not identical to autoimmune disease with autoantibodies. Peptides and proteins also behave as signals. Previous research on vasoactive intestinal peptide (VIP) has shown benefits in stopping inflammation. New research on PEPITEM shows such signals are also involved in recruitment of cytotoxic T-cells. We simply don't know how many more signalling molecules remain to be discovered.

 

[DeGenesis]

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.

 

[BurnA]

Autoantibody levels do not tend to correlate with clinical features in any autoimmune disease. This is presumably because only a subset of antibodies to an autoantigen are pathogenic and these are not reliably represented by binding in an in vitro assay.

While the autoantibody levels may not correlate has it been shown that the presence of certain autoantibodies correlate with specific symptoms ?

Would it be useful to document symptoms in relation to blood samples for biobank ? If there are possibly many CFS/ME subgroups with possibly different symptoms are the waters been muddied by pooling them all under the one group of patients ? or are there perhaps better ways to identify subgroups ?

 

[Hip]

@Jonathan Edwards
An idea about a possible mechanism of viral triggering of autoimmunity occurred to me today (one that does not involve molecular mimicry!); can I just run this by you, to see what you think.

When you get a viral infection of cells, this results in lysis of the cell, as the replicated viral particles within the cell burst out. Along with lysis, you get the lysate — the cellular debris that spills out of the ruptured cell. This lysate I presume will contain individual cellular fragments floating off into the bloodstream and lymph fluid.

My thought was that these free-floating cellular fragments might more easily elicit an antibody response against them (being mistaken for pathogens in the blood), giving rise to autoimmunity.

As a way of testing this idea: if it were true that viral cellular lysis could trigger autoimmunity, then you might expect the autoantibodies generated from a given viral infection would only be those that target antigens found on or within the cells that given virus can infect and rupture (every virus only has a small range of cell types it can infect).

So for each autoimmune disease suspected of being triggered by certain viruses, or associated with certain viruses, one could check to see if the autoantigens in that autoimmune disease were found in or on the cell types which the associated virus infects.

In the case of ME/CFS, this check actually comes out a positive: we know from Dr Chia's work that in the chronic enterovirus stomach infections found in many ME/CFS patients, it is the parietal cells of the stomach that the enterovirus infects. Now parietal cells possess both cholinergic and adrenergic receptors on their plasma membrane (ref: 1). So that works out, according to the theory, in terms of explaining why cholinergic and adrenergic receptor autoantibodies are found in ME/CFS.

In other words, when these parietal cells are ruptured by enterovirus infection and some cholinergic and adrenergic receptor cellular fragments may float away into the bloodstream, an autoantibody response to these receptors is created.

 

[Marky90]

@Hip that`s an really interesting hypophesis!

 

[Hip]

A further check reveals that parietal cells specifically express the beta-2 adrenergic receptor, but not the beta-1 nor alpha adrenergic receptors (ref: 1).

And parietal cells specifically express the muscarinic M3 cholinergic receptor, with no evidence they express the M1 or M2 receptors (according p112 of this textbook).


So that exactly ties in with Fluge and Mella's findings, namely autoantibodies against beta-2, M3 and M4 receptors in ME/CFS patients.

Except that a parietal cell infection does not seem to explain the M4 receptor autoantibodies, because as far as I could determine, the M4 receptor is not expressed on parietal cells.

The M4 receptor is primarily found in the brain, and it is possible that this hypothesized lysis-triggered autoimmunity might arise from enterovirus-infected brain cells. Enteroviruses are known to infect certain brain cells (including astrocytes and neural progenitor cells), and enterovirus infection has been found in the autopsied brains of ME/CFS patients.

The M4 receptor is also found in the urinary bladder (ref: 1), but I don't think that is involved in ME/CFS (except in patients with interstitial cystitis).

 

[Snow Leopard]

@Hip Have you read this paper:

https://www.researchgate.net/public..._B_lymphocytes_drive_human_autoimmune_disease

The key thing to note is the necessity of the self-antigen to be complexed to a foreign antigen - then when the B-cell receptor binds to the self-antigen, it can internalise it, but present the foreign antigen on the MHC, fooling the T-Cell into thinking the B-Cell is sensitive to a legitimate foreign antigen and leading to B-cell activation.

This begs the question about what complexes (between self proteins and foreign antigens) are possible and I would expect that antibodies against receptors hijacked for viral entry (endocytic pathways), along with scavenger receptors and the like, would be more commonly generated.

The main example in the Edwards paper is the RF - an antibody that targets other antibodies (which can be sensitised as those antibodies complex with foreign antigens).

 

[Jonathan Edwards]

@Jonathan Edwards
An idea about a possible mechanism of viral triggering of autoimmunity occurred to me today (one that does not involve molecular mimicry!); can I just run this by you, to see what you think.

When you get a viral infection of cells, this results in lysis of the cell, as the replicated viral particles within the cell burst out. Along with lysis, you get the lysate — the cellular debris that spills out of the ruptured cell. This lysate I presume will contain individual cellular fragments floating off into the bloodstream and lymph fluid.

My thought was that these free-floating cellular fragments might more easily elicit an antibody response against them (being mistaken for pathogens in the blood), giving rise to autoimmunity.

As a way of testing this idea: if it were true that viral cellular lysis could trigger autoimmunity, then you might expect the autoantibodies generated from a given viral infection would only be those that target antigens found on or within the cells that given virus can infect and rupture (every virus only has a small range of cell types it can infect).

So for each autoimmune disease suspected of being triggered by certain viruses, or associated with certain viruses, one could check to see if the autoantigens in that autoimmune disease were found in or on the cell types which the associated virus infects.

In the case of ME/CFS, this check actually comes out a positive: we know from Dr Chia's work that in the chronic enterovirus stomach infections found in many ME/CFS patients, it is the parietal cells of the stomach that the enterovirus infects. Now parietal cells possess both cholinergic and adrenergic receptors on their plasma membrane (ref: 1). So that works out, according to the theory, in terms of explaining why cholinergic and adrenergic receptor autoantibodies are found in ME/CFS.

In other words, when these parietal cells are ruptured by enterovirus infection and some cholinergic and adrenergic receptor cellular fragments may float away into the bloodstream, an autoantibody response to these receptors is created.

It's an idea that has been around for at least the last twenty years but I think it has some key missing links in the chain.

Remember that cells die in their billions every day - particularly blood cells and gut cells. So cells dying is absolutely an everyday phenomenon and fails to induce antibodies. When cells are killed by virus they are usually killed by your own cytotoxic cells and it is all fairly tidy. There may be cells that burst open but I am not sure that is actually the norm. When a cell spews out flu virus the virus is exported in a fairly tidy fashion. The mess yo see in viral lesions tends to be the inflammatory reaction.

And even if there is messier dying than usual the debris will not float into the bloodstream, since cells are outside the blood vessels. It will be picked up and carried via lymphatics to lymph nodes and spleen, just as dead cell material normally is. There is no reason for self cellular fragments to elicit an antibody response since the proteins involved will have been expressed in thymus, like all other proteins, during childhood, with deletion of necessary helper T cells and generation of relevant Tregs. 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.

The tissue specificity idea is reasonable. I think it is possible that it might apply to thyroid, where tissue specific antigens are recognised and where viral thyroiditis has been suggested as a trigger, although I am not aware of any thyroid specific viruses (there may be some). I do not think it works for the ACh and adrenergic receptors because these are everywhere - or at least on a very large number of different cells. So by your theory all viral infections should generate autoantibodies of this sort (there would be nothing special about herpes in parietal cells). Dr Chia's data would only support the theory if the receptors were specific to the target organ.