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

[anniekim]

This is where cohort definition is extremely important. Ideally, there needs to define their cohort and subsets (ie: viral onset, POTS or no POTS, early on in disease vs sick 10 years or more, etc. The larger the cohort, the larger subset numbers, the better .

Thanks Kati, defining cohorts does seem very important and not done enough. i am just wondering though if we are even looking at subsets but different diseases? I presume too early to tell.

 

[Kati]

Thanks Kati, defining cohorts does seem very important and not done enough. i am just wondering though if we are even looking at subsets but different diseases? I presume too early to tell.

There are certainly overlaps in our conditions. It's complicated.

 

[anciendaze]

I don't think it is time to write off the hypothesis of an infectious cause, though I'm sure it is not likely to meet the criteria of the IDSA. That is a matter of sociology rather than biology. As I've told others this is "an inconvenient disease" for everyone. It took about 40 years to get from the discovery of bovine leukemia virus to the admission that it really does produce slow infections in humans -- despite the close similarities with HTLV-1 and broad human exposure to the BLV virus.

The finding of polyclonal expansion of B-cells keeps turning up, though the pathogen to which these cells are responding may not be unique. An hypothesis that this clonal expansion is being exploited by a virus capable of replication without causing cell lysis still fits. Please note what BLV does in most cattle:

In general BLV causes only a benign mononucleosis-like disease in cattle. Only some animals later develop a B-cell leukemia called enzootic bovine leukosis. Under natural conditions the disease is transmitted mainly by milk to the calf. Infected lymphocytes transmit the disease too. So for artificial infection infected cells are used or the more stable and even heat resistant DNA. Virus particles are difficult to detect and not used for transmission of infection.

Is there a correlation between ME/CFS and unusual leukemias/lymphomas in humans? Considerable anecdotal evidence says there is. You'd have a hard time proving anything from official records which separate ME/CFS patients from all those with real diseases.

What is apparent in our human disease is that some subset of CD20+ B-cells is behaving strangely. It is possible to extract CD20+ B-cells via flow cytometry without killing them, and then experiment on these rather than complete patients. This kind of laboratory work is even used in treatment via adoptive immunotherapy for a number of cancers and some autoimmune diseases.

Many types of specialized immune cells pass through a stage where they present CD20+ epitopes. The current therapeutic approach is like a sledgehammer. We need a much better idea of which cells we need to deplete to break the pathology. It would also be nice to know what is going on inside them. In those cases where adoptive immunotherapy works like magic, without serious adverse effects, the targeted cells are likely to be those with a trio of distinctive epitopes.

These are generally targeted by stimulated cytotoxic T-cells or NK cells. There is some evidence of misdirection of such cells in ME/CFS. The immune system is behaving as if it is seeking a viral pathogen inside host cells, but it is not hitting the right target.

 

[mfairma]

I think the major American research groups need to take note that they are spending zero resources on studying the autoimmune pathophysiology of ME/CFS and this theory is not only the quickest and most promising path to effective treatment but also the quickest path to validation that this is a real disease. We patients need this.

I'm not sure that it is either correct or fair to say that American experts have spent no resources exploring autoimmune mechanisms. Klimas, for example, has attempted a number of times to get an IL-1 drug trial off the ground. But, I do agree. Further, your comment speaks to a deep problem that has held this disease back. Although this is beginning to change, we have a very small (and aging) pool of experts, many of whom (to their credit) have been involved in this disease for a very long time. Some may be too locked into outmoded understandings of this disease to really move us forward, especially at the rate demanded by the disease's severity and prevalence. We need a much larger pool of experts and much wider diversity of perspectives and expertise than we have now to achieve any remote parity of understanding with comparable diseases.

 

[Dolphin]

As I've probably said on the forum before, I think a lack of money being raised privately is a big problem in terms of building research capacity. Only a percentage of research grants will get accepted by grant agencies. One needs money there so grants that don't get funded by the taxpayer get funded. Also, having data from small pilot studies usually is a big help for researchers going on to get grants from government agencies so again important to have capacity to fund small pilot studies.

The Solve ME/CFS Initiative previously did a useful service when they requested applications and funded some small studies. They haven't done that for a while, I presume because of a lack of funding. This means I'm not sure how easy it is for research not affiliated with some charities to get private funding in the US now.

Although saying this, at least there's a reasonable amount of private funding in the US overall. I'd like to see all countries trying to raise money privately for research.

 

[Sasha]

Couldn't agree more, @Dolphin.

Every now and again, someone on the forums will say, "What's the point in us donating a fiver here and there? We need government-level funding", and the point is that governments only fund a minority of research in any disease. There are millions of patients and we need to put all those fivers together - and then the big private donors will come along and chip in. We've seen this again and again in crowdfunding - small donors, then big donors, then governments get embarrassed and cough up some money too.

It's just happened again with the IiME rtx fund - they've got nearly £500k now and half of that is from lots of little donations, and half from a very generous charitable foundation.

 

[Marco]

@Jonathan Edwards

Conformational changes of receptors is new to me but I'm curious as to what your thoughts are. As far as I can tell the 3D structure of receptors changes between 'idling' and 'active' and autoantibodies can bind to any configuration in between which I take is linear (sic) rather than binary? I missed the point that the ME/CFS paper discussed conformation changes suggesting that 'long term stress' could lead to conformational receptor changes to which autoantibodies bind to. Yet the paper I referenced on cardiomyopathy suggests a much shorter term, more dynamic response in receptor 'structure' which might support a role for autoimmunity in exacerbation of symptoms after 'exertion'.

I was also struck by the suggestion that autoantibodies can either change or freeze the activation state of receptors e.g. 'idling' receptors are switched to active and active receptors are permanently 'confirmed' as active. It appears in the case of autoimmunity in dilated cardiomyopathy that the end result of agonistic autoantibodies to Beta 1 adrenergic receptors is that they are downregulated so the heart muscles don't receive the usual adrenergic/sympathethic nervous system stimulation?

Is it possible that a similar process results in ME/CFS patients' tissues (wherever) not responding to 'stressors' because the receptors are already 'occupied' and downregulated?

Any thoughts?

 

[Gemini]

Did it work for you? Did you have hypotension prior to this as well? Do other long timers experience this too, I wonder?

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.

 

[halcyon]

The chronic infection theory, in my personal opinion, if it even pans out at all, will only be relevant for a small subset and one could argue that this subset isn't really even ME/CFS, it's an infection by a particular pathogen (e.g. Lyme, Chagas, etc).

I'd say it's the other way around since ME was clearly defined based on the infection triggered form of the disease, whether endemic or epidemic. If this is different and has nothing to do with infections then it would make more sense to describe it as some type of novel autoimmune disease. Again, as they point out in the paper, the majority of patients have (or appear to have) an infection triggered onset. I don't understand why you think this is such a small subset.

As we have seen in so many examples, post-Ebola, post-polio, post-sepsis, West Nile induced myasthenia gravis, likely many cases of post-Lyme, and more, that the infection isn't there anymore but it helped to trigger a disease that's now completely driven by the immune system.

Except that there is evidence for viral persistence in post-Ebola and post-polio.

 

[Jonathan Edwards]

Do we know if any diseases can be cured with Ritux? I know cancers can be put into remission, but how about RA and autoimmune diseases?

About a third of patients with immune thrombocytopenia appear to go into long term remission.

@Jonathan Edwards

Conformational changes of receptors is new to me but I'm curious as to what your thoughts are. As far as I can tell the 3D structure of receptors changes between 'idling' and 'active' and autoantibodies can bind to any configuration in between which I take is linear (sic) rather than binary? I missed the point that the ME/CFS paper discussed conformation changes suggesting that 'long term stress' could lead to conformational receptor changes to which autoantibodies bind to. Yet the paper I referenced on cardiomyopathy suggests a much shorter term, more dynamic response in receptor 'structure' which might support a role for autoimmunity in exacerbation of symptoms after 'exertion'.

I was also struck by the suggestion that autoantibodies can either change or freeze the activation state of receptors e.g. 'idling' receptors are switched to active and active receptors are permanently 'confirmed' as active. It appears in the case of autoimmunity in dilated cardiomyopathy that the end result of agonistic autoantibodies to Beta 1 adrenergic receptors is that they are downregulated so the heart muscles don't receive the usual adrenergic/sympathethic nervous system stimulation?

Is it possible that a similar process results in ME/CFS patients' tissues (wherever) not responding to 'stressors' because the receptors are already 'occupied' and downregulated?

Any thoughts?

I have not read the paper for the thread yet, as preoccupied with a few things. I think all these sorts of things are possible.

 

[leokitten]

I'd say it's the other way around since ME was clearly defined based on the infection triggered form of the disease, whether endemic or epidemic. If this is different and has nothing to do with infections then it would make more sense to describe it as some type of novel autoimmune disease.

Many of us here on PR have predicted that ME/CFS as a name will disappear in the future as we discover what the true illness(es) really are, and these illness(es) will get more appropriate names.

Again, as they point out in the paper, the majority of patients have (or appear to have) an infection triggered onset. I don't understand why you think this is such a small subset.

Please read what I actually wrote, that is not the small subset I'm talking about, in fact I have written many posts mentioning growing evidence of infections seeming to help trigger autoimmune disease. But in all of these diseases the infection goes away and the body continues to have autoimmune disease, it is not a chronic infection. The small subset I wrote about, if it even pans out, is a cohort of people who have a chronic infection which causes ME/CFS-like symptoms.

Except that there is evidence for viral persistence in post-Ebola and post-polio.

By definition post-Ebola and post-polio syndromes are not due to viral persistence, they are a different disease I think you should read up on them. If you still have either virus then you still have ebola or polio, not the syndromes above. A person still having Ebola in immune privileged areas such as their eye and testes is not post-Ebola syndrome.

 

[Hip]

By definition post-Ebola and post-polio syndromes are not due to viral persistence,

According to this study, this study and this study your statement is neither true "by definition", nor true in terms of actual empirical findings, as all these three studies found mutated poliovirus genomes in the CSF of post-polio syndrome patients.

Those three studies do not prove the mutated poliovirus is actually causing post-polio syndrome; but we certainly cannot say at this stage that post-polio syndrome is categorically not due to viral persistence.

 

[halcyon]

Many of us here on PR have predicted that ME/CFS as a name will disappear in the future as we discover what the true illness(es) really are, and these illness(es) will get more appropriate names.

If multiple pathogens or other causes can lead to the same underlying pathology then the underlying pathology will likely still have it's own name and definition. I understand what you're saying though and I partially agree.

Please read what I actually wrote, that is not the small subset I'm talking about, in fact I have written many posts mentioning growing evidence of infections seeming to help trigger autoimmune disease.

You assume that the 'infection triggered' and 'chronic infection' groups are different but we don't know this for sure yet.

By definition post-Ebola and post-polio syndromes are not due to viral persistence

I guess I should have been more clear but that's what I was getting at. 'Post' is possibly a misnomer or is at least misapplied in many patients with these diseases. They have pulled poliovirus RNA out of post-polio patients' CSF many decades after the initial infection. Medicine probably needs to rethink what these post infectious diseases actually are.

 

[Hip]

Prof @Jonathan Edwards:

Regarding this latest finding of autoantibodies targeting the muscarinic M3 and M4 receptors, and adrenergic β2 receptor in ME/CFS, plus previous ME/CFS studies which have found autoantibodies targeting the muscarinic M1, dopamine D2, mu-opioid and serotonin 5-HT1A receptors:

Does this data suggest that any autoimmunity in ME/CFS is likely based on a type 2 hypersensitivity reaction — ie, one which involves autoantibodies binding to antigens on cells (rather than the type 3 hypersensitivity found in rheumatoid arthritis, which I understand involves autoantibodies forming circulating immune complexes)?

If ME/CFS autoimmunity does in involve type 2 hypersensitivity, might that suggest that treatments which have some efficacy for other type 2 hypersensitivity autoimmune diseases might also potentially be beneficial for ME/CFS?

The only thing was, when I looked at treatments for various type 2 hypersensitivity diseases, I could not find much.

 

[leokitten]

According to this study, this study and this study your statement is neither true "by definition", nor true in terms of actual empirical findings, as all these three studies found mutated poliovirus genomes in the CSF of post-polio syndrome patients.

Those three studies do not prove the mutated poliovirus is actually causing post-polio syndrome; but we certainly cannot say at this stage that post-polio syndrome is categorically not due to viral persistence.

The vast majority of evidence on PPS has shown that it is caused by overload, i.e. supertraining. After the acute polio infection kills many motor neurons the remaining ones create additional sproutings to reenervate muscle fibers and take on more load. Decades after the acute infection these motor neurons eventually become overloaded and dysfunctional, leading to additional neuron death and the symptoms and neuropathy of PPS.

PPS always occurs decades after the original infection. I wonder if there was persistent poliovirus infection in the CNS then why are patients symptom-free for many decades before having any problems?

That being said apologies I shouldn't have put PPS in the list of diseases making my point because it doesn't really belong.

 

[Hip]

PPS always occurs decades after the original infection. I wonder if there was persistent poliovirus infection in the CNS then why are patients symptom-free for many decades before having any problems?

That is certainly a good question; I suspect it may be a result of immune senescence, which occurs with advancing years.

I shouldn't have put PPS in the list of diseases making my point because it doesn't really belong.

Even for some of other post-infectious syndromes on your list, there is no clearcut evidence for either way as to whether the syndrome might be due to a hit and run infectious trigger, or the long term presence of a chronic infection. See: Possible Persistence of West Nile Virus Infection.

As for post-Lyme, the jury is still out, as animal research has demonstrated the long term presence of a chronic Borrelia infection, and the question now is whether or not this animal research translates to humans.

And in conditions such as Ebola, there may not be enough research to even say with any certainty whether there is long term viral persistence or not. Here is what Vincent Racaniello wrote about the long-term effects of Ebolavirus infection on his blog:

These results confirm that there are long-term sequelae of Ebolavirus infection. The basis for the complications is not known, but is likely a consequence of tissue damage due to viral replication and the immune response. Whether or not virus was present in the patients was not determined. However it is known that Ebolavirus can persist in the testicles and eye long after it is absent from serum.

 

[Mya Symons]

For the scientists or medical professionals here: Is there some lab tests that we could get currently that would help us determine if we are likely to be responders?

For example, I found this through an online laboratory:
Immunoglobulin G, Subclasses (1-4)

 

[Snow Leopard]

For the scientists or medical professionals here: Is there some lab tests that we could get currently that would help us determine if we are likely to be responders?

For example, I found this through an online laboratory:
Immunoglobulin G, Subclasses (1-4)

This test doesn't really mean much unless you have disease which causes a specific type of immunodeficiency (and thus very low levels of one or more of the IgG subclasses).

It is finding antibodies directed towards specific targets that matters.

 

[A.B.]

Should we be testing for adrenergic and muscarinic receptor antibodies? If so, which tests are recommended?

Even if it's too early to recommend treatment, merely identifying the problem with reasonable confidence would already have a positive effect on our situation.

 

[Sasha]

Should we be testing for adrenergic and muscarinic receptor antibodies? If so, which tests are recommended?

Even if it's too early to recommend treatment, merely identifying the problem with reasonable confidence would already have a positive effect on our situation.

Is that something that we should be trying to make happen, @Jonathan Edwards?

While we're waiting for the clinical trial results, we have to bear the burden of being widely seen as having a psychosomatic disease, and that's a terrible burden on top of having such an awful illness. If a lot of us show up as having this biomarker it could help change the conversation.

We need not just to get rtx treatment in a timely way if the science backs it up: we need to try to dig ourselves out of this horrible situation that the BPS school have put us in in the meantime.