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

[Gemini]

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)

Good point.

From Abstract "A high correlation was found between levels of autoantibodies and elevated IgG1-3 but not with IgG4" along with HLA-DR+ T cells, thyreoperoxidase, and ANA.

Could testing these in combinationt begin to define a subgroup? @Snow Leopardand others any thoughts?

 

[Research 1st]

Sasha, unfortunately the answer is simple:

These specialist antibody tests are not commercially available, and therefore you cannot 'test' even if you wanted to.

Although it's infuriating, this is a common problem in scientific research (scientific knowledge) being well ahead of the game in doctor's offices (clinical practice).

The adrenergic and cholinergic antibody receptors (which also cannot be sourced for POTS patients either, since the 2014 paper with Dr Kem in the USA) copy the phenomena of non- legitimacy we are stuck with. E.g. If we look at another impressive finding in CFS research, we have the same problem of no assay we can get our hands on there either. This one, also from 2014:

Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome and Multiple Sclerosis
http://www.omicsonline.org/neurology-neurophysiology-abstract.php?abstract_id=25722

Which concluded:

the decreased production in those with CFS was unexpected and a novel finding. This finding could reflect
a reduced ability to maintain neuronal structure and function in those with CFS. Future studies are needed to
evaluate for neuronal damage in those with CFS

One idea to over come this:

If a start up company (e.g. group of interested parties) allied to a private lab would like to offer these tests as a 'kick-starter', idea them I'm sure the patients would oblige to pay for it.

https://www.kickstarter.com/learn?ref=nav

Do we know anyone though? I doubt we do: There must be someone out there though:

It could be sold as a 'research only' test to adults who sign a consent form agreeing to this. And thus, it would not need to be accredited,as it wouldn't be diagnostic, simply for personal interest.

After all, for the patients, it's a matter of live or death. We clearly have many diagnosed with ME CFS who have a brain disease, an autoimmune disease, and suffering the consequences of having no belief in their symptoms as organic. Subsequently we have no funding, so no research, and no treatments.

For many with organic ME CFS, the most worrying aspect to social psychiatry endangering their lives with an untreated disease state (other than inducing suicidal ideation) is suffering from cardiac arrythmias, seizures and immune supression leading to repeat infections. (Flu can kill the most healthy of people,never mind someone bedridden with reduced cardiac output, low blood volume and a brain autoimmune disease).

I think it's time the patients stuck together with good quality researchers and private companies wanting to help, and took over the ranch where our identity has been obilterated.

There's a new sheriffs in ME CFS town - they're called Science.

 

[Research 1st]

Good point.

From Abstract "A high correlation was found between levels of autoantibodies and elevated IgG1-3 but not with IgG4" along with HLA-DR+ T cells, thyreoperoxidase, and ANA.

Could testing these in combination at least begin to define a subgroup? @Snow Leopard comment?

Of course, but subroup of what? We'd need to run that assay with the others, and then eventually with the pathogen behind it. 'Autoimmune disease' is often allied to an infection, and some even believe autoimmune doesn't exist separately from infection.

For those interested out of curiosity one finding of this paper (elevated IgG1-3) can be purchased online) or just get your doctor to order an IgG subclass test. Many ME CFS patients have done this for years. We get differing results though and some have elevated IgG4 (the opposite finding of this recent brain autoimmune disease paper).

This is the problem, as autoimmune disease for a non specific marker is rarely consistent. Parts of the screening tools for Lupus, for example, are found in people without Lupus! (Antiphospholipid antibodies). ME CFS patients can also have these (Anti cardiolipin antibodies and not have Lupus either) and high blood viscosity (sticky blood), but don't fit criteria for 'the' sticky blood (Hughe's Syndrome) or have histories of blood clots. Etc etc.

As an actual finding, the significance of antibodies to beta adrenergic and muscaranic cholinergic receptors are more interesting than the IgG subclasses .(It's not that they are irrelevant and can even help diagnose Fibrosis and immune suppression), it's just that many other non neurological conditions, including idiopathic, can cause elevated or depressed IgG1-4 also!

Conversely, having a neurological disease ME (non believed), with symptoms consistent with autoimmunity against the brain also involving dysautonomia (POTS) that research then providesevidence of presence of these neurological markers (antibodies to antibodies to beta adrenergic and muscaranic cholinergic receptors) in the same disbelieved and medically neglected group.... Well this becomes very interesting indeed, when other groups have found these before as well, so it's not a 'fluke' finding.

All hail Norway and intelligent oncologists who listen to their patients! Meanwhile, the UK is funded the Graded Exercise religionists 1/2 million pounds and zero pounds for Rituximab....

 

[snowathlete]

Rituximab was approved for use in RA in about 2007. The rationale for its use in autoimmunity is indeed still not well understood by many physicians. But when there are hundreds of practitioners using a drug and regularly meeting and exchanging experience practical issues tend to get sorted out. The problem for ME is that physicians who might treat it may not have this experience.

How (and when) do we get rheumatologists on-board; interested and believing in the disease, understanding the disease properly? Sounds like they will be best placed to treat the disease but I wonder how willing they will be..?

Of course, we benefit hugely from your being involved already @Jonathan Edwards

 

[Simon]

@Marco was ahead of the game when he posted earlier about how what matters isn't just the presence of antibodies, but the type of antibody - whether it's binding has any biological effect or not. The authors make the same point in the discussion section.

[bit of background from me for anyone who might want it:
Theoretically, there could be dozens (at least) of different autoantibodies against any one receptor (antibody binding sites are generated at random, and it's luck if any happen to fit): there isn't just one "anti-M4 cholinergic receptor antibody". (As opposed to measuring cytokines suchs as IL-2, where everyone has the same.) Some antibodies might bind and effectively do little more than decorate the receptor, while others might force or lock it into an active state, boosting receptor activity (an agonist) - or an inactive state, blocking receptor activity (an antagonist). For instance, healthy controls with autantibodies might have neutral forms of antibody with little or no bioligcal effect. That might explain why therer is substantial overlap between patients and controls (of course, another reason might be that autoantibodies play no role in the illness, but it should be possible to test this idea).]

Similar to our findings, in most other diseases autoantibodies are found in only a subset of patients with a wide overlap of levels in patients and controls.

Various studies analysed function and binding of antibodies against ß AdR and M AChR. In fact most studies on ß AdR antibodies in cardiovascular disease used a cardiomyocyte contraction assay (Wallukat and Schimke, 2014). Autoantibodies against β1 AdR in cardiomyopathy were shown to affect ligand binding and cardiomyocyte function similar to agonists (Herda et al., 2012). However, the impact of ß1 AdR antibodies on receptor function is quite complex as antibody binding to different epitopes and heterogeneous effects on receptor traffic and activity including antagonist effects were observed (Schulze et al., 2005; Turki and Liggett, 1995). In addition, non-functional antibodies were described mostly in healthy individuals (Bornholz et al., 2014). Further studies suggest that conformational epitopes are recognized by ß1 AdR autoantibodies, requiring a three-dimensional receptor structure to detect them, which is often not preserved when recombinant protein or peptide-based assays were used (Bornholz et al., 2013). Assays using living cells are, however, difficult to standardize and not well suited for clinical diagnostics. In the present study we used recombinant receptors as antigens which are stabilized to maintain their conformation.

 

[Sasha]

Sasha, unfortunately the answer is simple:

These specialist antibody tests are not commercially available, and therefore you cannot 'test' even if you wanted to.

Sorry, I wasn't very clear. I wasn't suggesting we should all rock up to our GPs and ask for a test, or try to get one done privately. I meant, should we be asking for a study that simply gathers a well-defined ME/CFS sample and does this test?

A research study, that is, not self-testing.

 

[Jonathan Edwards]

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.

Yes, I think it would be worth all groups working on ME cohorts to try to replicate this. These assays are quite widely available in research circles. There are probably commercially available kits.

 

[Sasha]

How (and when) do we get rheumatologists on-board; interested and believing in the disease, understanding the disease properly? Sounds like they will be best placed to treat the disease but I wonder how willing they will be..?

Of course, we benefit hugely from your being involved already @Jonathan Edwards

I saw a rheumatologist a year or two ago when I had some symptoms that might (but didn't) indicate an autoimmune disease and I was getting polite but not enormous interest from the consultant about the rtx ME work until I said the magic words "Jonathan Edwards" and he perked up immediately and sat up in his chair and started to pay serious attention. If you'd video'ed the consultation and turned the sound down you could have seen the transformation in his body language.

Being able to say that Jonathan is seriously involved in this is going to be huge for us, if we need rheumatologists.

 

[Sasha]

Yes, I think it would be worth all groups working on ME cohorts to try to replicate this. These assays are quite widely available in research circles. There are probably commercially available kits.

Brilliant! How can we get this going? What can we do?

 

[Jenny TipsforME]

Sasha, unfortunately the answer is simple:

These specialist antibody tests are not commercially available, and therefore you cannot 'test' even if you wanted to.

I've got a blurry memory that you can find out relevant genetic information on these receptors with 23andme. I don't have any background knowledge in auto antibodies or genetics so this could be hilariously wrong. Does anyone know what I'm thinking of? I think there's a thread on PR somewhere about muscaranic receptors. Perhaps the auto antibodies are completely separate from the genetic predisposition/epigenetics? This isn't something I've ever studied.

I thought the idea that we may have auto antibodies to different receptors is interesting though, it would explain similarities and differences between subgroups. I'm struggling a little to understand the science behind this but it seems worth struggling with.

From a practical point of view, if I took the assumption based on symptoms (acute viral onset, POTS, gastro symptoms) that this is a likely cause for me, does anyone know of anything that might improve my symptoms while waiting for rituximab to become available? Are there any medications/supplements which should be avoided with this sort of auto antibody problem?

 

[Jonathan Edwards]

Brilliant! How can we get this going? What can we do?

I think it will happen. Various relevant people will be meeting in a fortnight's time.

 

[Sasha]

I think it will happen. Various relevant people will be meeting in a fortnight's time.

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?

 

[voner]

I think it will happen. Various relevant people will be meeting in a fortnight's time.

are there any Americans involved in this meeting in a fort night?.... it's starting to seem like there's a group of European researchers with a focused collaboration, well there is no such thing going on in the United States. It would be nice to hear that there's some United States researchers collaborating with the Europeans.

 

[Gijs]

Professor Edwards, did you ever seen patiënts who used Rituximab getting a deadly form of encefalitis? It is a very dangerous drug isn't it?

 

[Sidereal]

Sorry, I wasn't very clear. I wasn't suggesting we should all rock up to our GPs and ask for a test

Sorry for the juvenile reply but for some reason your post made me think of a horde of pwME descending upon GP surgeries all over the realm.

WE WANT tests for the damn adrenergic and muscarinic antibodies OR ELSE... we're gonna quietly go home, lie down and crash for a few days.

 

[Simon]

Wow. I'm a big fan of replication and seeing researchers come together to discuss replication of an important new findings, so quickly, is frankly brilliant. Seems like a real step up for the field. Thank you.

Yes, I think it would be worth all groups working on ME cohorts to try to replicate this. These assays are quite widely available in research circles. There are probably commercially available kits.

Brilliant! How can we get this going? What can we do?

I think it will happen. Various relevant people will be meeting in a fortnight's time.

 

[Jonathan Edwards]

are there any Americans involved in this meeting in a fort night?.... it's starting to seem like there's a group of European researchers with a focused collaboration, well there is no such thing going on in the United States. It would be nice to hear that there's some United States researchers collaborating with the Europeans.

The European collaboration does not intend to exclude anybody further afield. I think it is just an attempt to capitalise on shorter distance and get researchers together to exchange samples as much as possible. It will also have an eye on EU funding opportunities. US researchers come over to Europe for meetings on a regular basis and there is excellent rapport. I am sure that collaborations would be set up without problems if it seemed useful to send samples from one to the other. There is also collaboration between US and Australia.

 

[Marco]

@Marco was ahead of the game when he posted earlier about how what matters isn't just the presence of antibodies, but the type of antibody - whether it's binding has any biological effect or not. The authors make the same point in the discussion section.

Thnaks Simon. I might have been ahead of the game if I'd properly read the paper and didn't come across these issues in a paper on dilated cardiomyopathy!. Still it's good that they discuss these caveats and their implications for interpretation up front before we all get carried away with wild speculation.

.... talking of which.

I'd posted exerpts from the dilated cardiomyopathy paper where patients had agonistic autoantibodies to B2 adrenergic receptors and that in that condition the agonistic effects of the antibodies result in downregulation of cardiac B2 adrenergic receptors. I suggested that if something similar occured in ME/CFS (not necessarily in heart tissues) then tissues/organs might not respond appropriately to stressors including exercise.

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? It's well known that elevated sympathetic and reduced parasympathetic (vagal) tone is considered a strong predictive risk factor for cardiac events in autonomic neuropathy often associated with diabetes. The implication seems to be that elevated sympathetic tone is causal but perhaps it's just a correlation with some autoimmune process being the main driver?

Increased sympathetic tone does seem to be the case in 'idiopathic' dilated cardiomyopathy and hypertrophic cardiomyopathy :

Autonomic nervous system activity in idiopathic dilated cardiomyopathy and in hypertrophic cardiomyopathy.

Our results indicated attenuation of parasympathetic activity and enhanced sympathetic activity in HC during the night, and also in IDC. Assessment of autonomic imbalance by analysis of heart rate variability may be useful for understanding the pathophysiology of cardiomyopathies.

http://www.ncbi.nlm.nih.gov/pubmed/8498373

(bold added but sounds somewhat familiar) :

Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review.

CONCLUSION:

FM patients show more HRV aberrances and indices of increased sympathetic activity. Increased sympathetic activity is only present in CFS patients at night.

http://www.ncbi.nlm.nih.gov/pubmed/23838093

Enough speculation!

 

[alex3619]

@Marco was ahead of the game when he posted earlier about how what matters isn't just the presence of antibodies, but the type of antibody - whether it's binding has any biological effect or not. The authors make the same point in the discussion section.

Quite. Most receptors are fairly large molecules, though there is limited access outside of the cell membrane. Antibodies bind to tiny areas with specific shape and charge, and bind less well to areas with slightly different shape and charge. Only a very small pieces of a receptor molecule (or molecule complex) would be bound. So the impact is critically dependent on exactly what epitope it binds to (with epitope being the specific shape and charge it binds to, typically amino acids but not exclusively).

 

[Gemini]

Of course, but subroup of what?

The article describes a potential subgroup of responders to the treatment not whether ME is autoimmune & what pathogen might cause it.

I think it does a brilliant job of describing the autoantibody discovery & additional information about available tests.