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

Scarecrow

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I saw that too and wondered if plasma cells are the oproblem why they do not use an antibody to knock out plasma cells.
I was wondering the same. You'd need an antibody that was as specialised as possible, taking out the plasma cells you want to target without affecting anything else too crucial. So that presumably would mean identifying an antigen unique to plasma cells.
 

alex3619

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Therefore, are we any closer to identifying responders ? Seems like they have identified a subgroup who are potential responders but that doesn't mean you are a non responder if you don't belong to this subgroup ?
Plasma cells are not effectively targeted with Rituximab, just their B cell precursors. So decline in autoantibodies is by attrition of plasma cells over time. I vaguely recall some plasma cells can have long lives. Repeat Rituximab treatments seem to increase the number of responders over time. There is no substitute for the phase III clinical trial to be completed - only then we will have much of the data we need to understand this. So we may have to wait until 2017 to get some of these answers.

In the end we may need to develop therapies against plasma cells directly, though I would prefer therapies to be targeted to specific plasma cells if we can do this. In the meantime there are other alternatives being looked at including cyclophosphamide.

PS What @Scarecrow said.
 

alex3619

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Fig 1C shows the correlation of the concentration of one autoantibody vs the concentration of another - I don't see how that shows cross-reactivity between autoantibodies and multiple receptors. Am I missing something?
Cross reactivity against highly similar targets is likely. They are making a case for a simplifying hypothesis is my guess. Rather than multiple autoantibodies, why not have one that cross reacts? The high similarity between receptor subtypes, plus the way antibodies bind to (typically folded) epitopes, means that they may bind to other epitopes. However the differences between the subtypes will change their 3D configuration, and so reduced binding to those types.
 

Gemini

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so many of our symptoms are potentially explained by these antibodies. Gut motility/IBS. Autonomic Function....
Alex might these antibodies explain why certain longtime patients myself included at 26 years with a history of hypotension go on to experience hypertension and spikes in BP? Topic is being discussed on other PR threads.

For patients with the antibodies would they affect the choice of anti-hypertension treatment-- beta blockers, ACE inhibitors, calcium channel blockers, angiotension II blockers, diuretics, etc.?
 
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I saw that too and wondered if plasma cells are the problem why they do not use an antibody to knock out plasma cells.
The problem is one of specificity, finding a receptor that the plasma cells uniquely express, that other cell types don't express.

Wikipedia mentions several markers that plasma cells express: CD27, CD138 and CD319. CD27 is not specific, since it is expressed on T Cells as well. CD138 likewise, is not specific and is not only expressed on some B cells and plasma cells but, it is a target for some anti-cancer drugs. CD319 seems to be a potential candidate though:
http://www.arthritis-research.com/content/15/6/R207
 

Countrygirl

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Alex might these antibodies explain why certain longtime patients myself included at 26 years with a history of hypotension go on to experience hypertension and spikes in BP? Topic is being discussed on other PR threads.

For patients with the antibodies would they affect the choice of anti-hypertension treatment-- beta blockers, ACE inhibitors, calcium channel blockers, angiotension II blockers, diuretics, etc.?
Thank you for asking as I would so love an answer to this. After more than 30 years of quite severe hypotension with the ME (possibly POTS) I have very high BP and, worst of all, massive and rapid hikes that have left me with permanent damage and prolonged periods (about three months at a time) of what I think the GP described as hypertensive encephalopathy. It seems that standing or sitting upright triggers this horrid problem. I'm on an ACE inhibitor but it is not helping much. I would love an explanation that I could then pass on to the doctor as she is out of her depth. I was advised by Prof Pinching that treating our new-onset hypertension as essential hypertension would only serve to exacerbate the sudden hikes and make a stroke more likely.
 
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I'm confused by the cross-reactivity statement:

Fig 1C shows the correlation of the concentration of one autoantibody vs the concentration of another - I don't see how that shows cross-reactivity between autoantibodies and multiple receptors. Am I missing something?
It is a logical leap based on lack of statistical independence of each of the tests (the different receptor binding assays).

Polyclonal antibodies tend to be somewhat cross reactive. I guess at the very least, their results mean the same biological process is generating all of these antibodies together.
 
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I'm confused by the cross-reactivity statement:

Fig 1C shows the correlation of the concentration of one autoantibody vs the concentration of another - I don't see how that shows cross-reactivity between autoantibodies and multiple receptors. Am I missing something?
I have not read the paper yet but demonstration of cross reactivity would need pre-adsorption experiments to show that one antigen depleted reactivity to the other. Cross reactivity is a property of individual immunoglobulin species. It can be detected in polyclonal sera but should not be confused with broad specificity of an antiserum due to different immunoglobulin species reacting with different antigens.
 

Gijs

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@Professor Edwards, Is it right to say that these patiënts with elevated anti-bodies (in this study) have an autoimmune disease (primary, secondary or at least a compenent)) ?
 

Marco

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Here's an interesting review paper for the science/biology literate (which excludes me) which discusses issues such as diagnostic difficulties and alternative treatment approaches which may be more specific and less invasive.

Diagnostic and therapeutic aspects of β1-adrenergic receptor autoantibodies in human heart disease

http://www.sciencedirect.com/science/article/pii/S1568997214001657

The subject matter concerns agonistic autoantibodies to the β1 adrenergic receptor in dliated cardiomyopathy so don't be too concerned about the pathological impacts but there are a number of interesting observations (even to me) which may be relevant to future ME/CFS research/treatment if the autoimmunity story pans out.

Here are some exerpts (probably best read in context but relevant to some of the current discussions I think) :

It is estimated that agonistic β1AR autoantibodies could be involved in up to 10% of cardiac morbidity in western societies. ........

It must finally be noted that depending on the detection method deployed agonistic β1AR autoantibodies can be also determined in up to 12% of healthy individuals [8] and [19].
So a comparison of this larger group against controls would have suggested no disease association?

However, based on the aforementioned structural data, one can assume that the receptor domain targeted by the autoantibodies presents one series of transient conformations when the receptor idles and another slightly different series of transient conformations when it undergoes activation by an agonist. Individual cocktails of β1AR autoantibodies present in patients or healthy individuals will bind and stabilise distinct subsets of these conformations, thereby “freezing” the receptor in a unique transient state of activity/inactivity, and thus exerting a unique impact on its function, which provides a plausible explanation for the inter-individual heterogeneity of the impact of β1AR autoantibodies on receptor functions. In general, β1AR autoantibodies present in the circulation of patients with chronic heart failure (CHF) appear to have higher levels/avidities and stimulate and/or sensitise the receptor (i.e. target conformational epitopes presented both by inactive receptors, which are then switched into an active conformation, and by active receptors, which are further stabilised). In contrast, β1AR autoantibodies present in the circulation of healthy individuals have lower levels/avidities and no significant effects on β1AR activity...

Thus, it is not the mere presence of β1AR autoantibodies that distinguishes DCM patients from healthy subjects, but a different impact of the autoantibodies on β1AR function most likely dependent on/related to the conformation of the targeted epitope. This fact needs to be taken into consideration when devising therapeutic and diagnostic strategies.
(my bold).

Not only is mere presence inadequate but this raises the possibility of something like exercise generating a transient form of the receptor to which a particular autoantibody will bind and thereby it's effect on receptor function?

Re diagnostics :

There is a strong argument that the entire domain changes its conformation during receptor activation/inactivation and in doing so presents a multitude of transient conformational epitopes, which are targeted by β1AR autoantibodies (see 3.2 and 3.4). As a consequence, the autoantibodies poorly cross-react with linear representations or denatured versions of the targeted receptor domain.

It appears that peptide-based immunoassays are much less sensitive and specific than cell-based assays and only detect a subset of positive patients [37]. This probably explains, why studies on the prevalence of β1AR autoantibodies in cardiac diseases have largely diverging results. In general, much higher figures are reported using peptide-based immunoassays [49] and [78] as compared to native cell-based assays [8], [15] and [24]. The discrepancy is currently blamed on a high rate of false positive results.
Mmm - something to consider in the current study? and how clinically practical is a diagnostic test based on 'native cell-based assays'?

DCM patients and healthy subjects are not discriminated by the mere presence of β1AR autoantibodies, but by a different impact of their autoantibodies on β1AR function (see chapter 3). Only the prevalence of agonistic β1AR autoantibodies is clearly correlated with increased morbidity and mortality in DCM [6]. Therefore the mere demonstration of β1AR-binding IgG in the blood of a patient or healthy individual does not provide a sufficient basis for diagnostic predictions or therapeutic decisions. It needs to be discriminated whether the autoantibodies stimulate the receptor or not.
More of the same but I suspect we're in for a long ride.
 

msf

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I think I´ve asked this question before, but I don´t remember if Prof. Edwards answered it. Could autoimmunity explain the transitory nature of ME symptoms?
 

msf

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Sorry, I should qualify that, could it explain how some ME patient´s conditions seem to be worsened by exercise and changes in diet?
 

alex3619

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Alex might these antibodies explain why certain longtime patients myself included at 26 years with a history of hypotension go on to experience hypertension and spikes in BP? Topic is being discussed on other PR threads.

For patients with the antibodies would they affect the choice of anti-hypertension treatment-- beta blockers, ACE inhibitors, calcium channel blockers, angiotension II blockers, diuretics, etc.?
There is an antibody induced hypertension I think . I have never investigated it. I have no idea about what changes in treatment choices this would mean, this might be in existing published literature.

I also have high BP, but with severe NMH. The BP partially compensates for orthostatic crashes.

PS eg http://www.hindawi.com/journals/bmri/2014/504045/
 
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@Professor Edwards, Is it right to say that these patiënts with elevated anti-bodies (in this study) have an autoimmune disease (primary, secondary or at least a compenent)) ?
They have a disease and they have autoimmunity, at least as measured by these tests. To say they have an autoimmune disease requires that we are sure there is a causal relationship between the two - or at least pretty sure. I think we need to see other bits of evidence to be that sure. At least it is highly possible.
 

snowathlete

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The search continues. They still have to find autoantibody targets for half the responders. I don't think this is over, just starting.
I agree, there is more to find. I hope that these findings will help them get the funding they need to carry on their search for the rest.

In terms of the current findings, I wonder how expensive it might be for other groups to attempt replication (adminstration of ritux aside) - anyone have any idea?
 

Gemini

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After more than 30 years of quite severe hypotension with the ME (possibly POTS) I have very high BP....I'm on an ACE inhibitor but it is not helping much...
Countrygirl thank you for your "hypertension" post on the other threads.

I didn't connect hypertension to ME/CFS until I read it, your replies from other patients, & a reference I found in the cardiac chapter of Hyde's "Scientific Basis of ME/CFS"(1992). During my recent ER visit & hospital stay in the cardiac/stroke unit, different BP drugs/doses were tried. Eventually I was diagnosed with essential hypertension & put on a beta blocker & ACE inhibitor.

However, reading about B-cells in the development of hypertension & a possible role for B-cell depleting treatments like Rituxan for hypertension:
www.ncbi.nlm.nih.gov/pubmed/26351030

raises the question of whether Rituxan might be highly beneficial to hypertensive ME patients giving further urgency to its trial &results?
 

Countrygirl

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"Gemini, post: 644613, member: 597"]Countrygirl thank you for your "hypertension" post on the other threads.
:nervous::bang-head: Other thread????? Oh dear! I don't remember that. My memory went west long ago and I so miss it. It gets worse. :cry:So sorry if I have repeated myself.

I didn't connect hypertension to ME/CFS until I read it, your replies from other patients, & a reference I found in the cardiac chapter of Hyde's "Scientific Basis of ME/CFS"(1992). During my recent ER visit & hospital stay in the cardiac/stroke unit, different BP drugs/doses were tried. Eventually I was diagnosed with essential hypertension & put on a beta blocker & ACE inhibitor.
Did it work for you? Did you have hypotension prior to this as well? Do other long timers experience this too, I wonder?

However, reading about B-cells in the development of hypertension & a possible role for B-cell depleting treatments like Rituxan for hypertension:
www.ncbi.nlm.nih.gov/pubmed/26351030

raises the question of whether Rituxan might be highly beneficial to hypertensive ME patients giving further urgency to its trial &results?
I would like to know this too.
 

Gingergrrl

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Am confused again... Is the subgroup that Rituxan might help those with hypertension or hypotension (like me.)? I have chronically low BP 80's/50's without meds to try to raise it. My entire autonomic system is shot to hell.

I have had extreme reactions to cholinergic meds on both sides of the spectrum (Mestinon and Benadryl) and have autoimmune thyroid (Hashimotos) two antibodies and also *extreme* reaction to epinephrine. Also have high IgM titers to EBV.

I had a doc (prior to this article) say I was a good candidate for Rituxan but I still do not understand why?! I did not do it for many reasons aside from the fact that I cannot afford it. But am trying to grasp from article if I really am in that subgroup?