Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptor in ME patients - Bynke, Bergquist et al -2020

[Kalliope]

Full title
Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – a validation study in plasma and cerebrospinal fluid from two Swedish cohorts

Journal
Brain, Behavior, & Immunity - Health

Authors
Annie Bynke, Per Julin, Carl-Gerhard Gottfries, Harald Heidecke, Carmen Scheibenbogen, Jonas Bergquist

Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear etiology and no clear diagnostic biomarker available.

This study support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.

No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

 

[Trish]

Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients.

Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.

This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.

We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n=24), only plasma from the second cohort (n=24) together with plasma samples (n=24) and CSF (n=6) from healthy controls.

All samples were analyzed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1-5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.

Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4- receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples.

These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

 

[Hutan]

Here's the main chart. Red is for controls, the green and blue are for two patient samples. The various autoantibodies are on the x-axis. The differences look a bit underwhelming in terms of being a cause of ME/CFS symptoms.

 

[Milo]

Full title
Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – a validation study in plasma and cerebrospinal fluid from two Swedish cohorts

Journal
Brain, Behavior, & Immunity - Health

Authors
Annie Bynke, Per Julin, Carl-Gerhard Gottfries, Harald Heidecke, Carmen Scheibenbogen, Jonas Bergquist

Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear etiology and no clear diagnostic biomarker available.

This study support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.

No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

Thank you for sharing @Kalliope. May i ask that you fix the typo in the title to read ‘beta’ and not ‘beat’?

 

[Sid]

The scatterplot looks like there's nothing there to hang your hat on.

 

[Snow Leopard]

Here's the main chart. Red is for controls, the green and blue are for two patient samples. The various autoantibodies are on the x-axis. The differences look a bit underwhelming in terms of being a cause of ME/CFS symptoms.

Yes, I'm not going to get excited about this one.

 

[Amw66]

Did they separate out POTS comorbidities ?

 

[Kalliope]

Thank you for sharing @Kalliope. May i ask that you fix the typo in the title to read ‘beta’ and not ‘beat’?

Oops. Thanks for spotting that @Milo !

 

[butter.]

b1 seems significant.

 

[ME/CFS Skeptic]

The differences look a bit underwhelming in terms of being a cause of ME/CFS symptoms.

The statistical (Wilcoxon) tests did show some significant differences after Bonferonni corrections, most clearly for the M4-Musc-Receptor. Unfortunate that the authors don't report results for the two patient cohorts taken together.

This, however, suggests that the small differences were not that important clinically:

Our correlation analyses found no significant correlations between antibody levels and any of the symptom scores, suggesting that associations between levels of adrenergic and muscarinic receptor-antibodies and symptomatology are complex or non-existing. […] This lack of clear correlation between antibody levels and clinical symptoms challenge the clinical relevance of autoantibodies to adrenergic and muscarinic receptors and their connection to the pathology of ME.

 

[Eagles]

Merged thread

Open Medicine Foundation: New OMF Funded Research Paper

https://www.omf.ngo/2020/08/15/new-omf-funded-research-paper/

August 15, 2020

From the Desk of Jonas Bergquist, MD, PhD

Uppsala University

Open Medicine Foundation (OMF) is pleased to share the published results of an exciting fully-funded study conducted under the direction of Jonas Bergquist, MD, PhD, Director of the ME/CFS Collaborative Research Center at Uppsala University.

This study was designed to validate the increase of autoantibodies observed in the blood of people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that was observed in a previous study. In addition, the study investigated potential differences in autoantibody levels in the blood and cerebrospinal fluid (CSF) of those with ME/CFS and healthy controls.

Autoantibodies are antibodies (immune proteins) that mistakenly target and react with a person’s own cell structures. The increased autoantibodies observed previously in the blood of people with ME/CFS appear to be targeting ‘signaling molecules’ (named adrenergic and muscarinic receptors) on cell surfaces that are responsible for regulating energy metabolism, immune system activation, muscle activity, heart muscle activity and neurocognitive function…

 

[FMMM1]

Merged thread

Open Medicine Foundation: New OMF Funded Research Paper

https://www.omf.ngo/2020/08/15/new-omf-funded-research-paper/

August 15, 2020

From the Desk of Jonas Bergquist, MD, PhD

Uppsala University

Open Medicine Foundation (OMF) is pleased to share the published results of an exciting fully-funded study conducted under the direction of Jonas Bergquist, MD, PhD, Director of the ME/CFS Collaborative Research Center at Uppsala University.

This study was designed to validate the increase of autoantibodies observed in the blood of people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that was observed in a previous study. In addition, the study investigated potential differences in autoantibody levels in the blood and cerebrospinal fluid (CSF) of those with ME/CFS and healthy controls.

Autoantibodies are antibodies (immune proteins) that mistakenly target and react with a person’s own cell structures. The increased autoantibodies observed previously in the blood of people with ME/CFS appear to be targeting ‘signaling molecules’ (named adrenergic and muscarinic receptors) on cell surfaces that are responsible for regulating energy metabolism, immune system activation, muscle activity, heart muscle activity and neurocognitive function…

I'd be very interested in @Jonathan Edwards take on this paper.

I'm not clear why you would pursue autoantibodies as a cause of ME after rituximab failed; rituximab wipes out antibody/autoantibody producing B-cells. OK a small percentage of people could have an autoimmune form of ME and that would appear to be very interesting i.e. provide insight into the disease mechanism generally.
Also, perhaps Jonathan has explained in the past that there could be antibody/autoantibody producing cells which are not wiped out by rituximab --- still some antibody/autoantibody production occurring post treatment with rituximab.

I vaguely recall discussion that this technique could be removing something else e.g. the "something in the blood".

Are the assessment indicators questionnaires --- did they use activity monitors?

 

[Jonathan Edwards]

I'd be very interested in @Jonathan Edwards take on this paper.

I'm not clear why you would pursue autoantibodies as a cause of ME after rituximab failed; rituximab wipes out antibody/autoantibody producing B-cells.

Rituximab does not deal with all B cell driven autoimmune diseases because it does not remove long lived plasma cells. In several autoimmune diseases autoantibodies are produced by short lived plasma cells, which die off, but that is not the case for all.

Much more importantly the difference in antibody levels between ME patients and controls is minimal and provides clear evidence for these autoantibodies NOT being a cause of symptoms. The lack of correlation with severity adds to that. I think it is disappointing that the improvement after immuno-adsorption is touted as evidence in favour. That seems likely to be a placebo effect.

We need better research than this. We need high profile research institutes to move away from promotional press releases and start talking like proper scientists. To be frank we need the critical patient community to be as tough on poor biomedical studies as on BPS studies.

 

[FMMM1]

Rituximab does not deal with all B cell driven autoimmune diseases because it does not remove long lived plasma cells. In several autoimmune diseases autoantibodies are produced by short lived plasma cells, which die off, but that is not the case for all.

Much more importantly the difference in antibody levels between ME patients and controls is minimal and provides clear evidence for these autoantibodies NOT being a cause of symptoms. The lack of correlation with severity adds to that. I think it is disappointing that the improvement after immuno-adsorption is touted as evidence in favour. That seems likely to be a placebo effect.

We need better research than this. We need high profile research institutes to move away from promotional press releases and start talking like proper scientists. To be frank we need the critical patient community to be as tough on poor biomedical studies as on BPS studies.

Thank you very much for your reply.