pattismith
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Dr Grubbs team ‘Strongly Suggests’ Autoimmunity in Dysautonomia
- Thread starter Belbyr
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Gingergrrl
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This is what the most current research is showing (that there is a huge autoimmune component or subset to POTS and that high dose IVIG can be an effective treatment). There are some excellent videos about this by Dysautonomia International with Dr. Jill Schofield.
In my case (as Learner1 mentioned), I had significant improvement with high dose IVIG and Rituximab but most of my autoantibodies did not go down (and I was no longer doing IVIG for quite a while at the time of the follow-up testing so this was not the issue).
Several of my Cell Trend autoantibodies either did go down (or actually went from positive to negative). BUT the two autoantibodies that I was positive for on the Mayo Panels (Anti GAD65 and N-type Calcium Channel Ab) remained positive. The anti GAD65 did go down after treatment from 1.6 to 0.08 (but was still strongly positive) and the Calcium Channel/LEMS autoantibody went from 0.05 to 0.06 (basically the same) but did not go down.
I have learned from my doctor and a lot of reading that Calcium Channel autoantibody levels do NOT correlate with symptoms. You can have high levels of autoantibodies but zero or minor symptoms and you can have low levels of autoantibodies and have disabling symptoms (like I did prior to treatment). You can also be sero-negative and not even show the autoantibody on a blood test (which was not the case with me but it can happen with the calcium channel autoantibodies).
My doctor (who is also Learner1's doc) thought that it was possible that no new autoantibodies had been made (b/c my B-cells were at zero for so long) BUT that prior autoantibodies were still showing up on testing but were no longer pathogenic or causing symptoms. This is just a theory though.
The bottom line in my case is that I had dramatic improvement from the treatments but it did not reflect in most of my autoantibody tests. (I also have Hashi's but those two autoantibodies constantly go up and down, do not relate to symptom severity w/my thyroid, and had no role in my treatment other than more proof of overall autoimmunity).
I hope that made sense!
pattismith
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About the A1 adrenergic receptors, I found that they may be involved in nightmare under the activation by noradrenaline at high level. (Noradrenaline is supposed low in brain during sleep).
I wonder if POTS patients experience nightmares? ( @Learner1 )
The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder.2002
Taylor F1, Raskind MA.
1Rainier Associates, Tacoma, WA 98467, USA.
Abstract
Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of posttraumatic stress disorder (PTSD).
Prazosin is an alpha1-adrenoceptor antagonist commonly used as an antihypertensive agent.
Because alpha1-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha1-adrenergic activity may be useful in the treatment of PTSD symptoms.
An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial.
Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score.
All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day.
The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha 1 antagonist prazosin for PTSD.
pattismith
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I am around 60 for AT1R, ETAR and alpha1 adrenergic R, but don't have POTS. ( I have currently Grave's hyperthyroidism )
So nothing actually can tell if these antibodies are related to POTS symptoms or are only part of the disease signature.
Many GCPR are interfering one with each other, so I believe diseases should be tested extensively for all the AAb panel to make the picture clearer (I don't know if Dr Grubbs did so for POTS), and should look for decreased antibodies levels as well (not only elevated levels).
They tried to do it in this study for some diseases:
https://forums.phoenixrising.me/thr...-immune-diseases-muscarinic-and-others.78303/
;;;
Gingergrrl
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That is so interesting, Patti, that your levels were so high yet you do not have POTS. Do you have tachycardia as part of your Graves Disease?
I think they are just barely scratching the surface of what all of these autoantibodies mean and how they connect to ME/CFS, POTS, and to other autoimmune, autonomic, and neuromuscular diseases. Some of these tests are only available in Germany and are not even conducted yet in the US which is bizarre to me. But the research is exciting and I continue to follow it to the best of my ability on PR and other autoantibody groups.
pattismith
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yes I have tachycardia, but it's just the result of my hyperthyroidism as it resolves with my antithyroids meds.
These Celltrend antibodies are still for research and their clinical significance is not clear yet.
With these antibodies, I should have hypertension + tachycardia that don't resolve with my antithyroid meds.
But I don't even have hypertension from my hyperthyroidism, which people often experience.
On the other hand, these antibodies + my antithyroid antibodies shows that I have currently a real dysregulation of my auto-antibodies production, so I consider them as a sign it's not just a thyroid disorder that I have but a more complexe disease. I have probably some other antibodies at play that I'm not aware of!
I failed a tilt, too.
I had some guesses as to why, but I didn't know to think about periods.
Gingergrrl
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Thanks and I was just curious if your tachycardia fully resolved with your thyroid med alone. Do you have the Hashimoto's autoantibodies or only the ones for Graves Disease?
I also have the Cell Trend Autoantibodies (and want to compare mine to yours) but I have never had hypertension in my life. My BP runs very low and prior to treatment it was 80/50 every day for several years. If it reaches 100/70 now that is high for me. I also usually have a low, very screwed up pulse pressure (the systolic minus the diastolic BP).
I agree.
My doctor believes that I have a lot more autoantibodies but that finding more would not have changed my treatment plan so we stopped looking.
pattismith
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Like you I always had low blood pressure, so now I'm 100/60 which is also high for me!
I have all of my antithyroid Ab high (TPO, TG, TSHR), so for now I have Graves thyroiditis, but I may end with Hashimoto...This is not unusual.
I don't want to follow the normal protocol to manage the disease (high dose of antithyroid meds + T4 supplementation), because I can't tolerate high dose of these antithyroid drugs (headache, muscle problems, and my white cells are dangerously lowered)....So I do my own treatment plan with free iodine diet + low dose antithyroid meds and I have to look closely to my blood T3 and Ab levels to adjust.
I saw my endo yesterday, but he is not used to this kind of plan and can't help me on this.
Hopefully he is a nice old doc, and wasn't rude on me for doing things my way...
pattismith
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Is postural tachycardia syndrome an autoimmune disorder? And other updates on recent autonomic research
Is postural tachycardia syndrome an autoimmune disorder?
Whether autoimmunity is involved in the pathophysiology of postural tachycardia syndrome (POTS) is a controversial and still undefined topic.
When autoantibodies against ganglionic nicotinic acetylcholine receptors were first identified 20 years ago, it became clear that high titers were associated with severe autonomic failure including orthostatic hypotension, tonic pupils, and gastrointestinal and bladder abnormalities, a syndrome now referred to as autonomic autoimmune ganglionopathy (AAG).
However, some patients with POTS also tested positive with low titers [13]. Autonomic experts now agree that positivity for ganglionic nicotinic antibodies at low titer (i.e., below 0.2 nmol/L) has no clinical relevance for POTS, as these can be detected in up to 5% of healthy controls [9, 12, 14].
More recently, three groups (one at the University of Oklahoma, one at Lund University in Sweden, and one at University of Toledo in Ohio) have reported elevated antibodies against different G-coupled protein receptors (GCPRs) in patients with POTS [3, 5, 7, 15].
These studies found that, compared to controls, the vast majority of patients with POTS had serum antibodies against α-adrenergic and β-adrenergic receptors, and various subtypes of muscarinic, and angiotensin II receptors.
These studies, consistently small (no more than 20 patients even in spite of the fact that POTS is highly prevalent in the general population), are not devoid of methodological limitations and difficulties when interpreting the results.
Indeed, the most important criticism is the lack of correlation between the function of these autoantibodies and the phenotype of POTS. If these autoantibodies activated ubiquitous α1-adrenergic receptors throughout the autonomic system in patients with POTS, patients should suffer not only from tachycardia, which is the defining finding of POTS, but also hypertension, piloerection and urinary retention, among other manifestations.
And so on with the other identified antibodies against β-adrenergic, muscarinic, and angiotensin antibodies.
From a physiology point of view, it would be certainly challenging to imagine what would happen in a patient in whom all these receptors were activated and/or inhibited at the same time by these putative autoantibodies.
The group at the University of Oklahoma also found the same antibodies in multiple, disparate disorders (e.g., orthostatic hypotension, atrial fibrillation, and primary aldosteronism [4, 6, 16]) suggesting that their findings do not appear to be disease-specific.
Others argue that while these autoantibodies may not have a direct pathogenic role in POTS, they could reflect:
(1) some degree of immune dysregulation given that GPRCs play a role in regulating the innate immune system [11];
(2) an immune response to tissue injury; or
(3) some type of physiological regulatory response to cardiovascular stress.
Answering these questions is relevant for therapeutic reasons: disorders unequivocally caused by an autoimmunity (e.g., myasthenia gravis, Graves’ disease) respond well to immunomodulatory treatments. In any case, at this time, adrenergic, muscarinic and angiotensin receptor antibodies have not been proven to be causative or useful in confirming a diagnosis of POTS.
An important limiting factor in exploring the mechanisms of autoimmunity in POTS has been the lack of an animal model.
In their study recently published in the Journal of the American Heart Association, the University of Oklahoma group report the use of an animal model to investigate the role of adrenergic autoimmunity on the cardiovascular system [8]. Using a rabbit model previously employed in prior mechanistic cardiovascular studies, the authors tested the hypothesis that antibodies against the α1-adrenergic and β1-adrenergic receptors may be involved in the pathophysiology of POTS.
They immunized eight rabbits with peptides of the α1-adrenergic and β1-adrenergic receptors with boosters at 2 and 4 weeks to elicit antibodies against these epitopes. They then performed cardiovascular autonomic testing in the rabbits, including ECG and intra-arterial blood pressure measurements on a tilt table, as well as phenylephrine (an α-adrenergic agonist) and isoproterenol (a non-selective β-adrenergic agonist) infusions to examine the functional effects of the receptors. Each rabbit served as its own control.
At 6 weeks after immunization, heart rate increased by 17 bpm on head-up tilt, compared to the rabbits’ pre-immune baseline (27.8 ± 3.3% vs. 18.9 ± 1.5%; P < 0.05). The heart rate increase was suppressed by custom-designed antibody-neutralizing peptidomimetic inhibitors that specifically target the antibodies and block their interaction with the receptors. There was no significant change in blood pressure on tilt testing. During the phenylephrine injection after immunization, heart rate responses were significantly attenuated, suggesting a negative allosteric effect of α1-adrenergic antibodies, while the heart rate was significantly increased with isoproterenol, suggesting a positive allosteric effect of the β1-adrenergic antibodies. The authors found similar results using an in vitro cell-based bioassay, with rabbit sera obtained at the same timepoints as their in vivo analysis: before immunization, 6 weeks after immunization (before and after antibody-neutralizing peptide injection), and 30 weeks after immunization (after continued boost and antibody-neutralizing peptide treatments). They found an approximately 0.5-fold increase in α1-adrenergic anitbody activity and a 10-fold increase in β1-adrenergic antibodies activity after immunization, and a reduction to pre-immune baseline activity in the presence of the antibody-neutralizing peptides. These findings suggest that these adrenergic antibodies in rabbits indeed induced tachycardia, which was suppressed by custom-made antibody-neutralizing peptides.
The article is certainly interesting although some limitations must be noted. The animal model used appears to be good to study baroreflex function; however, it tells us nothing about the other multiple manifestations that patients with POTS suffer from. While it is speculative to compare any animal model to the heterogeneous clinical realities of POTS in humans, nevertheless, the rabbit model appears to be the most reasonable methodological choice. It would have been interesting to see the effects of inoculating serum from a patient with POTS who tested positive for these antibodies in a healthy rabbit, or, at least, whether serum from a rabbit containing autoantibodies could elicit tachycardia in a healthy rabbit. Moreover, the authors used no negative control, which would have been useful to ensure that the increased in heart rate was not just due to the rabbits experiencing the stress of undergoing multiple inoculations over several weeks. There was no placebo arm to compare the effects antibody-neutralizing peptide activity.
Hence, the greater conceptual questions still remain: are these autoantibodies, which seem ubiquitous in the serum of POTS patients, a mechanistic cause of disease or rather a bystander effect of the disease process? If the autoantibodies are causative, should we expect evidence of autonomic failure due to tissue destruction at some point in the natural history of POTS, as we see in autoimmune autonomic ganglionopathy (AAG)? These are questions that are vigorously debated within the autonomic community and, as always, further studies are needed. Nonetheless, this study is an important step in the continued investigation of the role of autoimmunity in POTS. More importantly, it offers hope for potential customized immunological therapies, but only if these autoantibodies are confirmed to cause POTS.
Skin biopsy for autonomic syndromes: time to look beyond nerve fiber density
(see next in the link)
Is postural tachycardia syndrome an autoimmune disorder?
Whether autoimmunity is involved in the pathophysiology of postural tachycardia syndrome (POTS) is a controversial and still undefined topic.
When autoantibodies against ganglionic nicotinic acetylcholine receptors were first identified 20 years ago, it became clear that high titers were associated with severe autonomic failure including orthostatic hypotension, tonic pupils, and gastrointestinal and bladder abnormalities, a syndrome now referred to as autonomic autoimmune ganglionopathy (AAG).
However, some patients with POTS also tested positive with low titers [13]. Autonomic experts now agree that positivity for ganglionic nicotinic antibodies at low titer (i.e., below 0.2 nmol/L) has no clinical relevance for POTS, as these can be detected in up to 5% of healthy controls [9, 12, 14].
More recently, three groups (one at the University of Oklahoma, one at Lund University in Sweden, and one at University of Toledo in Ohio) have reported elevated antibodies against different G-coupled protein receptors (GCPRs) in patients with POTS [3, 5, 7, 15].
These studies found that, compared to controls, the vast majority of patients with POTS had serum antibodies against α-adrenergic and β-adrenergic receptors, and various subtypes of muscarinic, and angiotensin II receptors.
These studies, consistently small (no more than 20 patients even in spite of the fact that POTS is highly prevalent in the general population), are not devoid of methodological limitations and difficulties when interpreting the results.
Indeed, the most important criticism is the lack of correlation between the function of these autoantibodies and the phenotype of POTS. If these autoantibodies activated ubiquitous α1-adrenergic receptors throughout the autonomic system in patients with POTS, patients should suffer not only from tachycardia, which is the defining finding of POTS, but also hypertension, piloerection and urinary retention, among other manifestations.
And so on with the other identified antibodies against β-adrenergic, muscarinic, and angiotensin antibodies.
From a physiology point of view, it would be certainly challenging to imagine what would happen in a patient in whom all these receptors were activated and/or inhibited at the same time by these putative autoantibodies.
The group at the University of Oklahoma also found the same antibodies in multiple, disparate disorders (e.g., orthostatic hypotension, atrial fibrillation, and primary aldosteronism [4, 6, 16]) suggesting that their findings do not appear to be disease-specific.
Others argue that while these autoantibodies may not have a direct pathogenic role in POTS, they could reflect:
(1) some degree of immune dysregulation given that GPRCs play a role in regulating the innate immune system [11];
(2) an immune response to tissue injury; or
(3) some type of physiological regulatory response to cardiovascular stress.
Answering these questions is relevant for therapeutic reasons: disorders unequivocally caused by an autoimmunity (e.g., myasthenia gravis, Graves’ disease) respond well to immunomodulatory treatments. In any case, at this time, adrenergic, muscarinic and angiotensin receptor antibodies have not been proven to be causative or useful in confirming a diagnosis of POTS.
An important limiting factor in exploring the mechanisms of autoimmunity in POTS has been the lack of an animal model.
In their study recently published in the Journal of the American Heart Association, the University of Oklahoma group report the use of an animal model to investigate the role of adrenergic autoimmunity on the cardiovascular system [8]. Using a rabbit model previously employed in prior mechanistic cardiovascular studies, the authors tested the hypothesis that antibodies against the α1-adrenergic and β1-adrenergic receptors may be involved in the pathophysiology of POTS.
They immunized eight rabbits with peptides of the α1-adrenergic and β1-adrenergic receptors with boosters at 2 and 4 weeks to elicit antibodies against these epitopes. They then performed cardiovascular autonomic testing in the rabbits, including ECG and intra-arterial blood pressure measurements on a tilt table, as well as phenylephrine (an α-adrenergic agonist) and isoproterenol (a non-selective β-adrenergic agonist) infusions to examine the functional effects of the receptors. Each rabbit served as its own control.
At 6 weeks after immunization, heart rate increased by 17 bpm on head-up tilt, compared to the rabbits’ pre-immune baseline (27.8 ± 3.3% vs. 18.9 ± 1.5%; P < 0.05). The heart rate increase was suppressed by custom-designed antibody-neutralizing peptidomimetic inhibitors that specifically target the antibodies and block their interaction with the receptors. There was no significant change in blood pressure on tilt testing. During the phenylephrine injection after immunization, heart rate responses were significantly attenuated, suggesting a negative allosteric effect of α1-adrenergic antibodies, while the heart rate was significantly increased with isoproterenol, suggesting a positive allosteric effect of the β1-adrenergic antibodies. The authors found similar results using an in vitro cell-based bioassay, with rabbit sera obtained at the same timepoints as their in vivo analysis: before immunization, 6 weeks after immunization (before and after antibody-neutralizing peptide injection), and 30 weeks after immunization (after continued boost and antibody-neutralizing peptide treatments). They found an approximately 0.5-fold increase in α1-adrenergic anitbody activity and a 10-fold increase in β1-adrenergic antibodies activity after immunization, and a reduction to pre-immune baseline activity in the presence of the antibody-neutralizing peptides. These findings suggest that these adrenergic antibodies in rabbits indeed induced tachycardia, which was suppressed by custom-made antibody-neutralizing peptides.
The article is certainly interesting although some limitations must be noted. The animal model used appears to be good to study baroreflex function; however, it tells us nothing about the other multiple manifestations that patients with POTS suffer from. While it is speculative to compare any animal model to the heterogeneous clinical realities of POTS in humans, nevertheless, the rabbit model appears to be the most reasonable methodological choice. It would have been interesting to see the effects of inoculating serum from a patient with POTS who tested positive for these antibodies in a healthy rabbit, or, at least, whether serum from a rabbit containing autoantibodies could elicit tachycardia in a healthy rabbit. Moreover, the authors used no negative control, which would have been useful to ensure that the increased in heart rate was not just due to the rabbits experiencing the stress of undergoing multiple inoculations over several weeks. There was no placebo arm to compare the effects antibody-neutralizing peptide activity.
Hence, the greater conceptual questions still remain: are these autoantibodies, which seem ubiquitous in the serum of POTS patients, a mechanistic cause of disease or rather a bystander effect of the disease process? If the autoantibodies are causative, should we expect evidence of autonomic failure due to tissue destruction at some point in the natural history of POTS, as we see in autoimmune autonomic ganglionopathy (AAG)? These are questions that are vigorously debated within the autonomic community and, as always, further studies are needed. Nonetheless, this study is an important step in the continued investigation of the role of autoimmunity in POTS. More importantly, it offers hope for potential customized immunological therapies, but only if these autoantibodies are confirmed to cause POTS.
Skin biopsy for autonomic syndromes: time to look beyond nerve fiber density
(see next in the link)
Gingergrrl
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Yes (in my opinion
). Actually in most of my doctor's opinions as well except it is not known yet if it is just a sub-group of POTS or all POTS. This is one of the most interesting and exciting areas of research to me (if POTS will ultimately turn out to be an autoimmune disease in the future).Hopefully some day it will no longer be undefined or controversial.
And Cell Trend & Dr. Scheibenbogen's research in Germany.
It's a bummer that the studies are so small with only 20 patients in them.
Also, and this is just anecdotal and not from a study, I belong to a group on FB for people all over the world who test positive for the N-type Calcium Channel Autoantibody (like myself) and almost 100% of the people also have POTS.
That was particularly interesting to me and I have seen and experienced immunomoduatory treatments in myasthenia gravis, LEMS, etc, but I had not heard of them being used for Graves Disease. I have Hashimoto's (not Graves) but my Endo told me that there are no immunomodulatory treatments for Hashi's (at this point in time) vs. disease management and symptom control with Thyroid medication (and things like avoiding gluten).
What is an example of a "custom-made antibody-neutralizing peptide"? I see the word "peptide" in a lot of threads but am not totally clear what this means?
pattismith
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Thank you for reading this article Ginger, we have not reach the point where scientists all agree on the auto immune nature of POTS, but I think we are on the good road, even some more works are needed!
I was surprised too not to be offered any immunosuppressive drug to help my Graves thyroiditis.
As I couldn't tolerate the betablockers nor the antithyroid drugs, I found helpful to take some cortisone and lipoic acid together with a nutritional approach, and my Graves slowly resolved. So I am convinced the multimodal therapeutic way is worth a try in this particular disease were the course is often spontaneously positive but not always.