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

[voner]

This is actually very weak evidence. Its association not causation. Even presuming we have an autoantibody issue, there remains a range of autoantibodies that have yet to be found. The actual causative autoantibody, presuming there is one, could be one of the ones not found yet. Which might explain why the antibodies found in this study were only found in less than half of the responders.

So the current antibody findings might explain disease causation in a subset, or be contributory, or be irrelevant....

the possibility of the researchers not finding the causative antibody would seem to also explain why some of the patients that responded to rituximab did not have elevated antibodies prior to treatment as stated in this quote from the paper that both Simon and I have flagged ...

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

i'm also still struggling with the concept stated by Jonathan Edwards that auto antibodies that are elevated are not commonly correlated to the symptoms (Here I'm assuming that "clinical features" are the same as "symptoms") but you have a study with a ME/CFS patient group selected purely on symptoms, but then how do you select what autoantibodies to test for if the selection is not based upon symptoms? I must be missing something.

 

[Bob]

I suppose it's possible that ME involves a large range of autoantibodies. I've now developed gut symptoms, POTS, joint inflammation/pain, general pain, and other symptoms that I never had during the first ten years of illness. I wonder why? Am I churning out new types of autoantibodies as part of the same illness? It seems like I've now had two different and distinct types of ME, but why? What does it mean? Have I had two different but closely related illnesses, or am I producing new types of autoantibodies as part of a single illness? And why would ME patients have different types of autoantibodies from each other and over time in the same person, if we do? What would that say about the illness mechanism? Do other autoimmune illnesses produce a range of different autoantibodies that can vary over time? Are ME patients particularly vulnerable to the production of new types of autoantibodies? And if so, why?

 

[Bob]

I agree with @snowathlete in that I'd very much like to see research looking for new types of autoantibodies in ME patients. But I don't know much about this field of research, so I don't know if it would be a productive enterprise.

 

[alex3619]

Does this paper tell us anything worthwhile ?

Oh, yes. It does indeed show that responders have lower antibody levels, and that nonresponders don't. It also shows which antibodies might be important in a subset. What it does not do is prove causation, but then it was never intended to. Its a place to start that journey, not the end of the journey.

What this study shows can be considered indicative of probable antibody impact. Its just that we need to be careful not to over-interpret it, and to advocate for more research funding and political will to take these findings forward. This could indeed be the Holy Grail as I indicated in an earlier post, but it might also just be an old cup.

 

[alex3619]

How about a rotten tomatoes type website for scientific studies where members of the scientific community can rank or critique academic papers based on certain criteria?

I'm surprised it doesn't already exist.!

Lol, that would be an interesting site. There are retraction watch sites, but those are for papers already recognized as bad and have been retracted from publication.

 

[alex3619]

Are ME patients particularly vulnerable to the production of new types of autoantibodies?

Maybe, but I really doubt it would be higher in any meaningful way or we would all be dead.

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.

It might however be the case that antibody levels lower than clinically significant might combine impact with other antibody problems. So people with ME might have two or more not very damaging antibodies, but combined they do enough to push beyond a tipping point. Its also the case that a combination of this and dysbiosis, or nonlytic pathogens, or toxins, or other things, might combine synergistically, and not in a good way. Some of these might also change over time.

We do however seem to have a high rate of B cell turnover. Maybe that makes a difference, maybe its very important.

Too many questions. Further studies might demonstrate more answers, though with our luck they might just generate more questions than answers.

 

[Kati]

My question with the non-responders, why their antibody didn't come down, would that be because in influence of other antibodies? Would it be due to Rituximab blocades at receptor site? Would it be a reservoir issue? Or would it cause production of more antibodies?

So much work is needed. I wish these non-responders would be offered Cyclophosphamide.

 

[brenda]

I suppose it's possible that ME involves a large range of autoantibodies. I've now developed gut symptoms, POTS, joint inflammation/pain, general pain, and other symptoms that I never had during the first ten years of illness. I wonder why? Am I churning out new types of autoantibodies as part of the same illness? It seems like I've now had two different and distinct types of ME, but why? What does it mean? Have I had two different but closely related illnesses, or am I producing new types of autoantibodies as part of a single illness? And why would ME patients have different types of autoantibodies from each other and over time in the same person, if we do? What would that say about the illness mechanism? Do other autoimmune illnesses produce a range of different autoantibodies that can vary over time? Are ME patients particularly vulnerable to the production of new types of autoantibodies? And if so, why?

A change in my symptoms after numerous years, which included joint inflammation and general pain, proved to be the contraction of Lyme disease.

 

[Hip]

My question with the non-responders, why their antibody didn't come down, would that be because in influence of other antibodies? Would it be due to Rituximab blocades at receptor site? Would it be a reservoir issue? Or would it cause production of more antibodies?

I understand it is because plasma cells, not B cells, create antibodies and autoantibodies. B cells turn into plasma cells, so by deleting B cells, the idea is that eventually you get rid of the plasma cells.

@Alex and @Scarecrow talked about this earlier:

Plasma cells are not effectively targeted with Rituximab, just their B cell precursors. So decline in autoantibodies is by attrition of plasma cells over time. I vaguely recall some plasma cells can have long lives. Repeat Rituximab treatments seem to increase the number of responders over time.

I think that are at least two reasons why the autoantibodies are not declining in some of the non responders. If there are more, hopefully someone else will join in.

1. The longevity of plasma cells ranges from days to years, or perhaps even decades. So, even though the B cells have been taken out, the source of the autoantibodies may still be present.
2 Some B cells may persist in reservoirs where rituximab cannot reach. That means that new plasma cells can still be generated even though the B cell population has largely been suppressed.

See also this thread: Long-Lived Plasma Cells in Autoimmunity: Lessons from B-Cell Depleting Therapy

 

[alex3619]

So much work is needed. I wish these non-responders would be offered Cyclophosphamide.

So far as I know there is research on cyclophosphamide in progress. However its years behind Rituximab, so we wont have a good answer as to its effectiveness for that much longer.

 

[Research 1st]

I think this research is going well now, very well.

Everything we needed to gain legitimacy is slowly coming to fruition, albeit now untold numbers patients are dead due to the inter continental 'agreement' to define and control research via a crippling disease via weak 'fatigue' criteria!

Despite this treachery, thanks to a tiny group of cancer researchers in Norway, not the CDC who are meant to 'control disease' and naturally never could with Fukuda CFS as the disease and militant psychiatry as the therapy, we have:

*A drug that works far better than placebo in people not even screened with an antibody screening test yet!

*A drug that doesn't work in the chronic severely affected (thus proving severely affected exist biologically - further destroying sceptical theory of patients only becoming severe due to self 'taken to bed' theory by external influences).

*A reason the drug doesn't work (immune damage due to length of illness and severity is obvious).

*Other ideas on drugs to attempt in these non Rituximab responder patients - excellent.

*Antibodies found in patients of which others likely exist that haven't been found yet (more ideas for research).

*Basic explanations why patients die (autoimmune diseases shorten life span).

*Basic explanation why patients have uncontrolled inflammation (very high chronic cytokines/chemokines are in severe 'CFS').

The people we have to thank is Monsieurs Fluge & Mella, and 'CFS' patient zero who apparently approached them after having cancer therapy drugs, and reported their 'CFS' was improved. If these two parties had never met, if Fluge & Mella has never listened to the patients, we'd never be where we are now - real hope!

In a way, this works out perfectly. By the time the pathogen papers come out, ME will be seen more and more as a legitimate autoimmune disease, as will POTS (by chance, a possible future 'cure' for autoimmune POTS is proposed already).

Test ME/POTS patients for the newly announced pathogen and it's finally over, maybe sooner than we think in terms of legitimacy (not treatment).

It will transpire we have a pathogen caused acquired immune deficiency leading to brain autoimmunity, leading to inflammatory cascade = brain nerve cell damage = Myalgic Encephalomyelitis. Due to the severity of the disease, it won't be able to be CFS. CFS will wilt away into the arms of the extremists and their 'ideas' of mind-body lies for the next generation of victims without medical aid.

I hope now, Dr Montoya will eventually be allowed to publish his findings (has a biomarkers to determine mild to severe disease) which he announced was imminent around March 2014.

In time researchers will be able to use this inflammatory biomaker of Dr Montoya's on autoimmune positive, vs autoimmune negative vs pathogen positive and this will bring even more answers!

Meanwhile we are told to go along with SEID without the inflammation, cancer ,autoimmunity or bran damage (Imaging studies and other markers associated with neuronal damage). I don't think so. I think the IOM left it far too late to pull that off. It's actually quite funny, how badly this desperate attempt to destroy ME quickly, went. (IOM said ME cannot exist as there is no evidence of inflammation, ignoring Dr Montoya's announcement that came out before the IOM study was even completed - and mysteriously never surfaced).

Thank heavens for Norway and these researchers who are free of the bounds of the IOM, CDC and British MRC and their 'fatigue' theories over chronic fatigue in people who don't have ME. Real biomedical research, always give you the answer when you measure not the tired people, but the people who are actually sick with a disease.

That's what CCC CFS / ME -ICC are for. Not F48.0 CFS and PACE bogus hogwash.

See the difference of theory vs science? We see it loud and clear and want more more more.

 

[Mya Symons]

@Jonathan Edwards

There is one part of the paper that has unclear significance. The degree of cross-reactivity of the antibodies to the GPCRs. The authors took particular care in gathering this data and making all the graphs, yet didn't say much about what the lack of specificity of the antibodies actually means in terms of their significance in causing symptoms and how they were induced in the first place.

What does this level of cross-reactivity indicate?

They did however say the following:


You previously mentioned that with experimental tests becoming increasingly sensitive, they may be detecting less specific antibodies. The implication is that that might not play a direct role in disease.

The study itself seems robust, with good sample sizes, and good statistical power (with α<0.001). But it doesn't look like this is the central finding that will allow the targeting of the use of Rituximab... (given that ME & CFS case definitions are subjective/nonspecific)

I'm wondering how important these particular findings are in the grand scheme of things, whether this is just a secondary effect of another dysregulation of the immune system? Especially since the same findings have been found in other autoimmune diseases which don't share the same set of symptoms.

I'm trying to understand this. Are you saying it is possible there is yet another undiscovered auto-immune disease causing the findings in this study (something not mentioned in the study)?

What are the chances that anyone will attempt to replicate this study in the U.S. or U.K.? Any ideas?

 

[MeSci]

Maybe, but I really doubt it would be higher in any meaningful way or we would all be dead.

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.

It might however be the case that antibody levels lower than clinically significant might combine impact with other antibody problems. So people with ME might have two or more not very damaging antibodies, but combined they do enough to push beyond a tipping point. Its also the case that a combination of this and dysbiosis, or nonlytic pathogens, or toxins, or other things, might combine synergistically, and not in a good way. Some of these might also change over time.

We do however seem to have a high rate of B cell turnover. Maybe that makes a difference, maybe its very important.

Too many questions. Further studies might demonstrate more answers, though with our luck they might just generate more questions than answers.

and is it possible that the disease process is actually one which triggers or facilitates the production of autoantibodies rather BEING than the production of the autoantibodies or what results from them?

• So: disease process triggers or facilitates autoantibody production?
• Disease process IS autoantibody production?
• Disease process results from autoantibody production?

• How much does it matter which autoantibodies are produced?
• Does the body have 'preferred' (auto)antibodies that it produces, or rather doesn't weed out of the stochastic production?

Thinking out loud, some questions perhaps verging on the philosophical, although they may have a bearing on treatment.

I think that @Jonathan Edwards would be best at answering this! Is it even possible that such different types of disease process might lead to the same or similar illness, as in Jonathan's fascinating and long thread here?

 

[ukxmrv]

I think that it is important to acknowledge that this research is coming out of TREATING patients with CFS with an experimental drug.

For decades we were told that couldn't get access to experimental drugs because little was known about the cause of our disease.

This was obviously wrong.

The findings here have only come to light because someone listened to a patient who had cancer and noticed that their CFS symptoms were better after that.

We could have done this decades before.

It shows that we never needed to know what caused CFS or ME to be able to treat it. It also shows that researching a group of patients who respond to a treatment can tell us about the disease process possibly underlying their disease.

There are other drugs being used by doctors treating CFS that we could be researching now.

 

[BurnA]

The findings here have only come to light because someone listened to a patient who had cancer and noticed that their CFS symptoms were better after that.

We could have done this decades before.

It shows that we never needed to know what caused CFS or ME to be able to treat it. It also shows that researching a group of patients who respond to a treatment can tell us about the disease process possibly underlying their disease.

There are other drugs being used by doctors treating CFS that we could be researching now.

What other drugs might work ?
Is it possible that a drug may be developed that targets or stops certain autoantibodies ?

Would any of these be likely to be effective in cfs ? http://monocl.com/consulting/2015/0...-the-bodys-own-disease-fighting-immune-cells/

 

[Valentijn]

What other drugs might work ?

I think low-dose corticosteroids are frequently used with autoimmune disease, as they suppress the immune system. They have been trialed in CFS patients by the psychobabblers with some success, though they never followed up on it and strongly advocated against their use in CFS.

Other methods are discussed at https://en.wikipedia.org/wiki/Immunosuppression and https://en.wikipedia.org/wiki/Immunosuppressive_drug

 

[BurnA]

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 ?

 

[Gemini]

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?

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?

 

[anciendaze]

On autoantibodies: you need to remember that immune response is a stochastic process, not directed by conscious decisions. We produce antibodies in response to things statistically associated with tissue damage, and some of these are infectious agents. Classical immunology talked about the distinction between "self" and "other", but this is very inadequate for processes at boundaries like mucous membranes. There are far more "other" organisms in our bodies than human cells, and we don't benefit from constantly attacking all of them.

Clonal expansion can produce a response that is exponentially greater than the stimulus, as required to deal with exponential expansion of infectious agents, and this appears to be deranged in autoimmune disease. Clonal expansion is also defective in leukemia/lymphoma, so it should have been natural to look for common factors in these classes of disease, and to follow the continuum of disease from lethal to chronic diseases. Why this did not happen, except in a tiny fraction of cases where remarkable coincidences appeared in exactly the right context, is a good question to ask about our dysfunctional medical and medical research institutions.

 

[alex3619]

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