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

snowathlete

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Loebel, Grabowski, Heidecke, Bauer, Hanitsch, Wittke, Meisel, Reinke, Volk, Fluge Ø, Mella, Scheibenbogen.

Abstract

Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder. We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.
 
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Note interesting Rituximab connection where elevated autoantibodies at baseline are normalised after treatment for rituximab responders .

Thanks, @snowathlete

Broken into paragraphs here to help my fuzzy brain - plus 'highlights'

Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome

Highlights
• β adrenergic and muscarinic acetylcholine receptor autoantibodies are elevated in a subset of patients with Chronic Fatigue Syndrome (CFS).

• Elevated autoantibodies in CFS correlate with elevated IgG1-3 subclass levels, thyreoperoxidase and ANA antibodies and T cell activation.

• In CFS patients responding to rituximab treatment, elevated antibody levels detected pre-treatment normalized in the majority of clinical responders post-treatment.


Abstract
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors.

Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases.

Method
Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against [G-protein coupled receptors] human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108).

Results

Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls.

A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4.

Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies.

In patients receiving rituximab maintenance treatmen
t achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.

We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy.

The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

One for @Jonathan Edwards?
 
Last edited:

snowathlete

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They're certainly looking in the right place and its a sizeable sample which is good. Would seem to predict half of those who respond to rituximab and suggests more to find in this area to figure out who else will respond. And of course it could significantly focus research efforts into mechanisms, and subsequently causes.
Look forward to what Prof Edwards makes of it.
 

ukxmrv

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or of POTS maybe?

"Epinephrine (adrenaline) reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoreceptors because there are more peripheral α1 receptors than β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, producing vasodilation followed by decrease of peripheral vascular resistance."

https://en.wikipedia.org/wiki/Adrenergic_receptor
 

Sidereal

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From the discussion:

We found significantly elevated levels of antibodies against ß2 AdR, M3 AChR and M4 AChR in a subset of patients with CFS. Some controls had elevated antibodies as well. In contrast, no difference between CFS patients and controls were found in antibody levels neither against α AdR described in hypertension (Dandel et al., 2013 and Wallukat and Schimke, 2014) dopamine receptors found in schizophrenia and movement disorders (Balint and Bhatia, 2013, Dale et al., 2012 and Steiner et al., 2015), serotonin receptors found in antiphospholipid syndrome (Frauenknecht et al., 2013), nor against endothelin or angiotensin receptor as in systemic sclerosis (Gunther et al., 2014), and thromboangiitis obliterans (Klein-Weigel et al., 2014). A previous study from Japan reported serum autoantibodies against the M1 AChR in 31 of 60 CFS patients (Tanaka et al., 2003). In a more recent PET study, evidence of M AChR autoantibody binding in the brain was provided by showing that antibody-positive patients had reduced binding of a labelled M AChR ligand as compared to antibody-negative CFS patients and healthy controls (Yamamoto et al., 2012).

Autoantibodies against ß AdR and M AChR have already been described for more than two decades in cardiovascular and more recently in various autoimmune and neurological diseases (Wallukat and Schimke, 2014). β1 AdR and M2 AChR antibodies were first described in patients with protozoa-induced Chagas heart disease (Davila et al., 2008, Labovsky et al., 2007, Ribeiro et al., 2010 and Thiers et al., 2012). ß AdR autoantibodies were further shown in patients with dilated cardiomyopathy, orthostatic hypotension, and POTS (Dandel et al., 2012, Li et al., 2014, Li et al., 2015, Wallukat and Schimke, 2014 and Yu et al., 2012). Antibodies against M AchR were described in autoimmune diseases including M1 in Lambert Eaton (Suzuki, 2010), myasthenia gravis (Takamori et al., 2007) and schizophrenia (Jones et al., 2014), and M1 and M3 in Sjögren’s Syndrome (Schegg et al., 2008 and Sumida et al., 2013), and β1 and M2 in Graves’ disease (Galloway et al., 2014 and Stavrakis et al., 2009). These diseases share similarities with CFS including fatigue and autonomic dysfunction. A study in schizophrenia showed binding of M1 antibody positive patients IgG in brain tissue especially in hippocampus, but not in M1 negative patients (Jones et al., 2014). M1 AChR knockout mice have severe deficits in learning and memory (Gould et al., 2015). 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.
 

Marco

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This is from a blog I wrote on complex regional pain syndrome :

An autoimmune contribution to CRPS now appears likely given recent findings that 90% of an adult CRPS cohort had autoantibodies (agonistic, therefore upregulating) to either the beta(2)-adrenergic receptor (β2AR) or the muscarinic acetylcholine receptor (M2R). Fifty percent of the cohort had autoantibodies to both. 10

The actions and distribution of these receptors closely match CRPS symptoms: β2AR or M2R receptors are found in the cerebellum, reticular formation, motor cortex, and thalamus in the brain, in the sympathetic and parasympathetic nervous system, the heart, the pyramidal motor pathway to skeletal muscles, in peripheral nerves, and in astrocytes and microglia.

Interestingly Alan Light’s team 11 recently found a threefold upregulation of gene expression for the adrenergic alpha2a receptor in ME/CFS patients following exercise. In addition, several studies have found autoantibodies to muscarinic acetylcholine receptors in ME/CFS 12, 13 and Sjogren’s Syndrome 14. Evidence for autoimmunity in FMS is scant but fibromyalgia does appear to occur co-morbidly in autoimmune diseases such as lupus, rheumatoid arthritis and autoimmune thyroid disease 15.
Read more: From Chronic Regional Pain Syndrome to Fibromyalgia to ME/CFS? The ‘Spreading Neuroinflammation’ Model http://www.cortjohnson.org/blog/201...lgia-mecfs-spreading-neuroinflammation-model/

These things seem to get around!
 

Sidereal

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I see that antibodies to muscarinic cholinergic receptors in ME patients were first found in 2003: http://www.ncbi.nlm.nih.gov/pubmed/12851722
They're not antibodies to the same muscarinic receptor. The Japanese study you linked found antibodies to M1 whereas this German/Norwegian collaboration found antibodies to M3 and M4. The Japanese study is cited in their paper.
 

Rooney

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• Elevated autoantibodies in CFS correlate with elevated IgG1-3 subclass levels, thyreoperoxidase and ANA antibodies and T cell activation.
While I have POTS, I have only had REDUCED IgG subclasses, so I imagine I would be a non-responder.
Is this a correct interpretation?

Wow, what an exciting morning!