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

[A.B.]

Some information about these receptors collected on Wikipedia.

Beta 2 adrenergic receptor:

Relaxation of smooth muscles. Smooth muscles are found on the walls of blood vessels, lymphatic vessels, the gastrointestinal (gut motility), respiratory (bronchi), and reproductive tracts, and a few other places.

Glucose production in muscle cells.

Insulin secretion by the pancreas.

Heart muscle contraction and cardiac output.

In the liver, breakdown of glycogen into glucose, and generation of glucose from non-carbohydrate sources. The liver stores stores most of our glucose reserves in the form of glycogen.

Increases renin secretion by the kidney.

Inhibit histamine release.

Muscarinic acetylcholine receptor M3:

Constriction of smooth muscles.

Paradoxically on endothelial cells, activation of this receptor leads to vasodilation, since the endothelial cells react by producing nitric oxide.

It regulates insulin secretion in the pancreas and is important for understanding type 2 diabetes.

M3 receptors are located on many endocrine (hormones) and exocrine glands (sweat, digestive enzymes, mucus, etc). Sounds like a recipe for nonspecific gut problems and HPA axis hypofunction.

Muscarinic acetylcholine receptor M4:

It functions as an inhibitory autoreceptor for acetylcholine. My understanding is that the purpose of this receptor is to make sure that cells in the brain don't secrete too much acetylcholine. PS: Could this explain hypersensitivity to stimulation?

 

[bertiedog]

It provides symptom relief in some patients, yes.

Might explain why I do so well on 6mg Prednisolone daily as I do have a dysregulation similar to POTS and also respond well to 20 mg Propananol which keeps my heart rate under control provided I don't have too much caffeine or too much heat.

When I was first put on hydrocortisone for adrenal insufficiency I didn't do as well as on the Pred and I have often wondered why that is.

Pam

 

[Valentijn]

M4 seems to be a bit ominous. Only found in the brain, seems to be involved in extrapyramidal motor control via dopamine.

Maybe that would explain the subgroup of ME patients who have PEM from cognitive activities but not from physical exertion.

 

[Dolphin]

RRTI = what? (Table 1, patient characteristics)

 

[Dolphin]

Canadian ME/CFS criteria used.

 

[Dolphin]

Good to see:

these samples were analysed blinded to group allocation (CFS patients versus controls, responder versus
non-responder, pre- versus post-treatment).

 

[Dolphin]

We observed diminished serum levels of at least one immunoglobulin class or subclass in a total of 27.1% of CFS patients according to the reference range of the Charité diagnostic laboratory, and elevated serum levels in 20.9%, respectively. The most prominent finding was a single or concomitant IgG3 (10.1%) deficiency in CFS patients.

 

[Dolphin]

We further correlated elevated receptor autoantibodies with various clinical symptoms including disease severity, muscle pain, susceptibility to infection and infection triggered disease onset. The only association we observed was of M1 AChR antibodies with dizziness (p=0.05). Data on POTS was available in 8 patients only. Of these 4 patients fulfilled the criteria for POTS and 4 did not. Elevated ß AdR antibodies were present only in two of the latter.

 

[Marky90]

I would be very thankful indeed, if somebody with the knowledge neccesary, could make a post illuminating the possible implications of this particular study. For the layman..

 

[Sidereal]

Data on POTS was available in 8 patients only.

This would be a fruitful area of future research, IMO. The subset of patients that have these antibodies, is there anything that clinically distinguishes them from the rest who also carry a CFS diagnosis, say prominent autonomic symptoms like POTS or NMH

 

[Dolphin]

Rituximab responders vs. non-responders:

View attachment 12760

Black circles (responder) and grey circles (non-responder) indicate patients with elevated β2 pre Rx levels. In patients with non-elevated β2 pre Rx levels circles are white.

 

[Dolphin]

Anyone know whether UCL antibodies study (precursor to proposed Rituximab trial) would be looking at these antibodies?

 

[Dolphin]

Remarkably, elevated autoantibody levels had normalized in the majority of clinical responder post-treatment. In responder posttreatment levels for all four antibodies were significantly lower compared to pre-treatment.

In the samples from non-responder there were significantly lower levels for ß1 AdR antibodies but no obvious difference between ß2, M1 and M4 levels pre- and post-treatment. Total IgG, IgA and IgM levels post-treatment were somewhat lower (mean 1.04, 0.28, and 0.27 g/l lower, respectively) as compared to pre-treatment levels, but the reductions were not significantly different between responder and non-responder (manuscript submitted).

 

[Dolphin]

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.

Is this true for all conditions? My impression was certain autoantibodies were very common in some conditions.

 

[Jonathan Edwards]

I would be very thankful indeed, if somebody with the knowledge neccesary, could make a post illuminating the possible implications of this particular study. For the layman..

I think Alex has given a pretty good summary.

We heard about these data in May at IiME but have had to wait keeping mum for Carmen to get things sorted for formal publication - which has been quite quick in fact. I need to look at the paper in detail but I think these are important findings. The only caveat to flag up is that muscarinic ACh receptor antibodies have a reputation for being a bit of a pain in terms of reproducibility but I would not worry too much about that. It is good to see dynamic results - i.e. changing with treatment. It is also great to see the Norwegian/German collaboration bearing fruit. There is a lot more work to do but this is very promising.

It is hard to answer the question about implications specifically. However, if it proves possible to select cases for rituximab based on data like this then that makes a huge difference to getting a therapeutic programme of the ground. One of the most important brakes on the programme is the worry that treatments like rituximab would have to be used hit and miss in a condition that is hard to pin down diagnostically and that may include people for whom this is the wrong approach. Take away that worry and treating ME by B cell targeting begins to look much more similar to lots of other diseases.

 

[Jonathan Edwards]

Is this true for all conditions? My impression was certain autoantibodies were very common in some conditions.

I think it is relative - and I think they are stretching the analogy a bit. As you say, in a lot of autoimmune conditions we have antibody tests that will pick up 60-95% of patients. There are some more muddly ones like vasculitis, but not so many.

 

[Marco]

More generally @Jonathan Edwards do these specific autoantibodies sound like the sort of thing you would expect given the clinical presentation? It all sounds a little too simplistic to me even if I did 'blog' about the possibility.

 

[Dolphin]

I thought TPO was related to thyroid but wasn't sure given how it was spelled

TG - thyreoglobulin
TPO - thyreoperoxidase

I think they may have used German spellings.
TG = Thyroglobulin
TPO = Thyroid peroxidase or thyroperoxidase

 

[BurnA]

Especially patiënts with POTS/ME will have this problem. I Always have suspected this. This is a breakthrough for a subgroup.

Could you explain why ?

 

[Jonathan Edwards]

More generally @Jonathan Edwards do these specific autoantibodies sound like the sort of thing you would expect given the clinical presentation? It all sounds a little too simplistic to me even if I did 'blog' about the possibility.

I think it does sound simplistic but I suspect there are layers of subtlety underneath and I am quite happy to think this might link to the clinical presentation. Everything in immunology tends to need looking at from a certain sideways angle to see how it really makes sense, but when it does I think it does.