Adrenergic Autoantibody‐Induced Postural Tachycardia Syndrome in Rabbits, 2019, Li et al

Open access here: www.ahajournals.org/doi/10.1161/JAHA.119.013006
Editorial here: www.ahajournals.org/doi/10.1161/JAHA.119.014084

Funded by Dysautonomia International. From their press release:

 

Well i have a positiv tilt table and also these antibodies. Getting a plasma exchange next week. So i can tell you pretty soon how imported that is haha

 

Could these autoantibodies also cause other CFS / ME symptoms like fatigue, PEM, etc. or do they only cause POTS?

 

Nice, let us know how it went. For patients in Europe, it seems almost impossible to get this treatment other than from paying it 100% of your own pocket.

Dr. Jonas Bergquist spoke in the latest OMF symposium about having found these autoantibodies in about 70% of their patients at Uppsala, shame there is no video record available of that online.

 

Then why haven't we heard anything about those antibodies for the last 20 years? And if the problem is indeed autoantibodies wouldnt rituximab have helped?

 

Probably the same reason we hadn't heard about the "something in the blood" factor messing up cellular metabolism in ME/CFS until Ron Davis came and did some actual research on ME/CFS patients. I believe Carmen Scheibenbogen was the first to discover these autoantibodies in ME/CFS/POTS patients and Bergquist is now replicating her findings it seems.

According to my doctor who has done collaboration with Uppsala, they have observed a correlation with some of these autoantibody titers and the disease, especially one muscarinic autoantibody, which also came out high in my test results. Sadly, there is no treatment offered yet as it's still research in progress. Regarding rituximab, it's a good question why it didn't work. Scheibenbogen has observed improvement in her trial using immunoadsorption.

 

Given that we still don't have an animal model for ME, and in light of the something in the blood findings plus the annoying debates over deconditioning, this is interesting:

https://www.ahajournals.org/doi/10.1161/JAHA.119.014084

But there's also a caution not to get too excited too soon:

https://www.ahajournals.org/doi/10.1161/JAHA.119.014084

 

I doubt it is worth speculating much about these antibodies. The differences in levels between controls and disease cohorts are not big enough to suggest a role in disease mechanism. When autoantibodies cause disease the differences are much more stark.

 

The negativ Rituximab trial doesnt rule out an autoimmune cause of ME/CFS at all. There a different types of antibody producing B-cells. Varying on each person they can be produced by earlier B-cells who still have an cd20 epitope or by long living plasma cells who dont react to Rituximab anymore. That was also one of the explanations Fluge gave why the trail could have failed. Also we are talking about antibodies who act like neurohormones. Its not like rheumatism where reducing the antibody count with Rituximab helps you because you reduce the inflammation. There is no real inflammation in ME/CFS. No real inflammation loop you could break through. So you better be off comparing it to something like morbus basedow. Where also antibodies act like hormones. So even a small count of antibodies could be enough to keep you ill. Thats where i dont go along with Edwards opinion.

"I doubt it is worth speculating much about these antibodies. The differences in levels between controls and disease cohorts are not big enough to suggest a role in disease mechanism. When autoantibodies cause disease the differences are much more stark."

I think we are talking about autoantibodies who act like neurohormones that make you sick. Compare this disease to something like primary Hyperepineprinemia or adrenal medullary Hyperplasia.

https://www.youtube.com/watch?v=w4s0uNy8Q2g

listen to him and tell me he doesnt sound like a guy with CFS

But instead of real adrenalin you get autoimmune made adrenalin which cant be measured the normal way. And even small doses make you really sick. Its an autoimmune made adrenaline poisoning in my opinion. Thats why i decided to undergo a plasma exchange treatment. Because if its right what im saying it should help me get better. At least for 1 week or so. As a proof of concept.

 

I wish you were correct, but if so, why were Prof. Scheibenbogens Immunadsorption studies not successful?

 

I talked with Dr. Scheibenbogen about the study. It also was just a proof of concept. 10 ppl got an immunadsorption with no further follow up medication or treatment. 9 out 10 said they got an improvement out of this ( mostly for around 2-3 weeks, just as long an immunadsorption without further treatment should help here ). And 3 out of 10 ppl still said they were improved after 1 year. Fr. Scheibenbogen said that she could show that in these 3 patients the count of long lasting plasma cells dropped significantly. So i would say its a pretty good sign for an autoantibody driven disease.

 

Yeah and IMO this is the way to go, at least from my engineer's perspective. Simply filter the autoantibodies from the blood and see what happens, if there is improvement you have demonstrated both a disease mechanism and a treatment. I don't know why others aren't pursuing it.

At least in Uppsala they are not looking just at the presence of autoantibodies, but the levels as well, to see if there is any correlation. But anyway, since there is already a method that can remove autoantibodies this selectively, I don't see why it's not hypothetically a superior treatment over rituximab, IVIG or immunsuppressive drugs.

 

Dear @Badpack
You make some valid points but there are a couple of things I would add.

Pretty much all effective soluble antibody is made by plasma cells, none of which have CD20. I was aware of that when we introduced rituximab for autoimmune disease. The rationale for rituximab is actually rather complex and has to do with the autoamplifying nature of an antibody response and the feedback role of antibody on further antibody production.

The lucky thing about many autoantibody producing plasma cells is that many of them are short lived. However, plasma cells making antibody to Ro and RNP for instance are not. Autoantibodies in ME might by from long lived plasma cells so the failure of rituximab does not prove ME is not autoantibody based.

But the plausibility of an autoantibody mechanism has to depend on at least some evidence. I have looked at data on muscarinic and adrenergic receptorsntibodies in ME and controls and the difference hardly detectable. That is not what you see in an autoimmune state that is well understood.

As Ivan Roitt used to say we all have a little bit of antibody to everything. Having something show up on a binding assay is a long way from showing pathogenic efficacy. If the amounts turning up are much the same as normals there is no real reason to think they are relevant.

I agree that autoantibodies would be acting as neurohormones in this case but I don’t see that as particularly different from arthritis or thyroid disease. (I don’t know what morbus basedow is. ) AndI don’t see how that would alter things. You may only need small amounts of antibody but if there are small amounts in normal people it does not take us far.

The problem with plasma exchange is that it only ever has a short lived effect and because of placebo responses and illness fluctuation it would be hard to tell if an improvement meant anything. I am fairly sure plasma exchange was tried in ME and it did nothing.

 

@Jonathan Edwards

Thanks for the response. Im not a native english speaker so please forgive me any mistakes i maybe make in showing my thoughts now. I didnt measure my autoantibodies with a standard binding assay to just show the amount or just the existence. I used a bio essay, a model with rat cardiomyocytes where the prepared serum was added. With different blockers you can rule out all the antibodies one after another. My ß2 response made the heart cells beat faster for around 40 beats. My muscarinic antibodies around 50 beats. So they have a real pathological role i would suggest.

I see a difference in ME vs. arthritis because you never get the arthritis antibody count to zero with rituximab. And frankly you dont have to because in lowering the count you make the patient a lot better because of the underlying inflammation you reduce. But i believe that with neurohormones, a bit better just isnt enough to help.

Morbus Basedow / Graves disease is an autoimmune disease where the body attacks the TSH receptors. For me its a great comparison because its the only known and proven autoimmune disease with neurohormone autoantibodies. And just like CFS no immunsupression shows any sign of improvement. Often the thyroid gland is just removed. This isnt a very doable venture with sympathetic/parasympathetic nerves. So it comes down to filtering/removing the antibodies for now till aptameres are out of clinical studies to do a better job at it. ( BC007 from berlinCures as an example or the ones used in this study above).

I found 3 plasma exchange case studies and all suggested a pretty good outcome. So im going to try it and we will see i guess.

 

@Hutan https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541141/ i used this method. Its a test for GPCR autoantibodies like seen in CFS. Because of the physiology of the heart you can measure around 15 different antibodies at the moment. Amongst other things a1, ß2, M2, nociceptin, AT1, ET.

So yeah my serum causes the equivalent of tachycardia in rat heart muscle cells, thats right.

 

The paper I have seen using that assay looks difficult to interpret. A bioassay of a human antibody using another species has a lot of potential problems. And that is particularly so for individual case findings. I think a standard binding assay is easier to interpret.

I still don’t see why residual amounts of antibody are more important in Graves. I remember a study where Graves responded well to rituximab. It is just easier to use surgery.

 

A randomised double blind controlled trial would certainly be possible and you would not need objective end points if blinded. I just think that better evidence for a link to autoantibodies is needed before exposin* people to the risks.

It is possible that there are different antibodies in ME but then the assays are not showing that up so the ME antibodies might be any sort of antibodies, unrelated to adrenergic or muscarinic receptors- so we are back to first base. If the assay does not pick out something associated with disease we cannot cherry pick and say what it picks out in PWME is special.

When I first mentioned to Angela Vincent, who is maybe the world authority on neuro autoantibodies, that someone had found neuro autoantibodies in ME she immediately said “I hope you are not going to say muscarinic”. I said “fraid so”. She said “oh dear”. End of conversation.