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

[dancer]

This paper sounds exciting, but is way over my head.

But the question it raised for me - don't many of us get a standard bunch of basic blood work when we first go in - and it all comes back normal? When this paper talks about ME/CFS patients with auto-antibodies, do those show up on a basic ANA blood test? If my ANA test hasn't been abnormal, does that mean I'm not a good candidate for B-cell depletion therapy?

 

[alex3619]

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 this is big enough that people will be posting stuff for weeks. At some point it will be time to summarize all that.

 

[Sidereal]

When this paper talks about ME/CFS patients with auto-antibodies, do those show up on a basic ANA blood test? If my ANA test hasn't been abnormal, does that mean I'm not a good candidate for B-cell depletion therapy?

No, these antibodies don't show up on an ANA screen. A subset of patients in this study were ANA+, however.

 

[alex3619]

If my ANA test hasn't been abnormal, does that mean I'm not a good candidate for B-cell depletion therapy?

No. Most responder patients probably had more or less normal ANA. ANA is just one of possibly millions of potential autoantibodies. In any case its not one of the critical autoantibodies here, though it was mentioned. We also have to wait for the phase III trial to be completed before we can say about who might or might not respond. That is another two years of research, at least.

There is no test that can broadly test for autoantibodies. There are secondary markers and subgroup titres that are suggestive, but nothing definitive. You have to go fishing for each one, and you better have the right bait.

 

[Riley]

Does anybody know anything about CFS research in Germany or the authors of this paper? This is the first paper I've seen out of Germany.

That would be fantastic if there's another group of researchers seriously pursuing CFS.

 

[ukxmrv]

Does anybody know anything about CFS research in Germany or the authors of this paper? This is the first paper I've seen out of Germany.

That would be fantastic if there's another group of researchers seriously pursuing CFS.

Dr Scheibenbogen has been coming to the Invest in ME conferences (London)

http://www.investinme.org/iime conference 2013/IIMEC8 Agenda.htm#Carmen

 

[msf]

Sorry, thought they might have said something at the conference.

 

[Sidereal]

Does anybody know anything about CFS research in Germany or the authors of this paper? This is the first paper I've seen out of Germany.

They've published on CFS previously and they also have an immunology clinic in Berlin where they diagnose patients.

Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

 

[TiredSam]

Dr Scheibenbogen has been coming to the Invest in ME conferences (London)

http://www.investinme.org/iime conference 2013/IIMEC8 Agenda.htm#Carmen

She's also speaking at the annual CFS/ME Conference in Dortmund today (26th Sept).

 

[alex3619]

I don't want to say much yet, it may be weeks before I can read much on this, but so many of our symptoms are potentially explained by these antibodies. Gut motility/IBS. Autonomic Function. I am looking at possibilities. I stress these are just possibilities, and not certainties. Of particular concern to me is alteractions in cAMP chemistry. I hope to look into that more.

 

[Kati]

I don't want to say much yet, it may be weeks before I can read much on this, but so many of our symptoms are potentially explained by these antibodies. Gut motility/IBS. Autonomic Function. I am looking at possibilities. I stress these are just possibilities, and not certainties. Of particular concern to me is alteractions in cAMP chemistry. I hope to look into that more.

I am interested at the adrenergic receptors, POTS and the fact that many of us, including me has horrible reactions to epinephrine, used for instance in local freezing at the dentist. Coincidence?

Edit to add: Dr Light mentions increased beta adrenergic gene expression following 2 days exercise test.

I'd say we are on a track...

 

[alex3619]

OK, a chain of speculation, with a chance of being wrong at each step.

Take beta 2 adrenergic receptors post exercise. If we presume an antibody knocks it out, the cell might register that its not having normal expression via one or more feedback mechanisms. At that point its possible that the cell may crank up production, causing a temporary massive increase. This will of course be a delayed response. So its possible that knocking out the receptors will in some cases lead to increased expression, with rapid shifts in symptoms.

Antibody damage is more like a war than an attack. The body tries to fight back, then the antibodies knockout more receptors, so the body makes even more, swinging back and forth on symptoms. Its like a war front that constantly moves back and forth, without going anywhere much. Think WW1.

Just speculation, but its something I want to think about. Biology is complex, and we do not know all the pieces of this puzzle, nor even if the current findings are really important.

 

[Marco]

Just an observation and not a criticism by any means - there's a limit to what they can test for - but I noticed that they tested for antibodies to serotonergic and dopaminergic receptors but not the gabaergic or glutaminergic pathways that are known to be associated with other suspected autoimmune disorders like stiff person syndrome (GAD antibodies) or anti-nmda receptor encephalitis.

 

[alex3619]

there's a limit to what they can test for

The search continues. They still have to find autoantibody targets for half the responders. I don't think this is over, just starting.

 

[BurnA]

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)

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.

One for @Jonathan Edwards?

Why wouldn't the autoantibodues decline in the non responders ?
Does this imply even if you have the elevated autoantibodies discussed here, they may not decline with RTX, therefore you will be a non responder?
So only a portion of the 29.5% would respond? In which case there is at least another 20-30% subgroup who may respond but we dont know why ?

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 ?

 

[Snow Leopard]

@Jonathan Edwards

There is one part of the paper that has unclear significance. The degree of cross-reactivity of the antibodies to the GPCRs. The authors took particular care in gathering this data and making all the graphs, yet didn't say much about what the lack of specificity of the antibodies actually means in terms of their significance in causing symptoms and how they were induced in the first place.

What does this level of cross-reactivity indicate?

They did however say the following:

Further we observed more than half of the patients having antibodies against more than one receptor of the respective family. This is not surprising as there is a 40 – 70% sequence homology within the five M AChR and within the two ß AdR and an approximately 30% overlap of ß AdR and M4 AChR. Furthermore, the presence of both M AChR and ß AdR autoantibodies is reported in other diseases as well (Galloway et al., 2014; Pei et al., 2012; Stavrakis et al., 2009; Talvani et al., 2006; Zhao et al., 2006). Our correlation studies suggest that the prime targets of antibody responses in CFS are ß2 and possibly M4 receptors.

You previously mentioned that with experimental tests becoming increasingly sensitive, they may be detecting less specific antibodies. The implication is that that might not play a direct role in disease.

The study itself seems robust, with good sample sizes, and good statistical power (with α<0.001). But it doesn't look like this is the central finding that will allow the targeting of the use of Rituximab... (given that ME & CFS case definitions are subjective/nonspecific)

I'm wondering how important these particular findings are in the grand scheme of things, whether this is just a secondary effect of another dysregulation of the immune system? Especially since the same findings have been found in other autoimmune diseases which don't share the same set of symptoms.

 

[Gijs]

@Jonathan Edwards

There is one part of the paper that has unclear significance. The degree of cross-reactivity of the antibodies to the GPCRs. The authors took particular care in gathering this data and making all the graphs, yet didn't say much about what the lack of specificity of the antibodies actually means in terms of their significance in causing symptoms and how they were induced in the first place.

What does this level of cross-reactivity indicate?

They did however say the following:


You previously mentioned that with experimental tests becoming increasingly sensitive, they may be detecting less specific antibodies. The implication is that that might not play a direct role in disease.

The study itself seems robust, with good sample sizes, and good statistical power (with α<0.001). But it doesn't look like this is the central finding that will allow the targeting of the use of Rituximab... (given that ME & CFS case definitions are subjective/nonspecific)

I'm wondering how important these particular findings are in the grand scheme of things, whether this is just a secondary effect of another dysregulation of the immune system? Especially since the same findings have been found in other autoimmune diseases which don't share the same set of symptoms.

Hasimoto is also be found in ME/CFS patiënts (secondary). Does this mean this finding isn't important either? NO.

 

[Scarecrow]

Why wouldn't the autoantibodues decline in the non responders ?

Antibodies are produced by plasma cells, which are differentiated B cells. The protein CD20 is attached to the surface of most B cells but not to plasma cells. Rituximab is a CD20 antibody, which is why it destroys B cells.

I think that are at least two reasons why the autoantibodies are not declining in some of the non responders. If there are more, hopefully someone else will join in.

1. The longevity of plasma cells ranges from days to years, or perhaps even decades. So, even though the B cells have been taken out, the source of the autoantibodies may still be present.
2 Some B cells may persist in reservoirs where rituximab cannot reach. That means that new plasma cells can still be generated even though the B cell population has largely been suppressed.

Disclaimer: I get most of my information from wiki or from sites that have copied wiki

 

[lansbergen]

Antibodies are produced by plasma cells, which are differentiated B cells. The protein CD20 is attached to the surface of most B cells but not to plasma cells. Rituximab is a CD20 antibody, which is why it destroys B cells.

I saw that too and wondered if plasma cells are the oproblem why they do not use an antibody to knock out plasma cells.

 

[Simon]

The degree of cross-reactivity of the antibodies to the GPCRs. The authors took particular care in gathering this data and making all the graphs, yet didn't say much about what the lack of specificity of the antibodies actually means in terms of their significance in causing symptoms and how they were induced in the first place.

What does this level of cross-reactivity indicate?

I'm confused by the cross-reactivity statement:

Crossreactivity between all 5 M and ß1 and ß2 AdR but also between M and ß receptor was seen in a substantial portion of CFS patients as shown for M4 in Fig. 1C. The highest correlation was found between M3 and M4 receptor antibodies (r=0.87), the lowest for M1 and M4 receptor antibodies (r=0.59).

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?