Bob
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Today, Thursday 15 Oct: Solve webinar with Dr Alan Light: New Developments in ME/CFS Research
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voner
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so... during the interval of about 24 minutes to 28 minutes into the video, Dr. Light talks about the beta2 androgenetic receptor, StrepA , the Close match of their receptor epitotes, and the possibility of molecular mimicry triggering an autoimmune response....
I would love to hear some comments, how about it @Jonathan Edwards, since you've expressed your doubts about Molecular mimicry in autoimmunity.
SpecialK82
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Yes, she mentioned Dane Cook (I believe it was in November?) but didn't catch the day if it was said.
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Wow what a waste of money, energy, time, thinking. Glad I didn't wake up for this, hah.
alex3619
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This is a good presentation but sometimes its a bit oversimplified, such as no mention of plasma cells with respect to the Rituximab response time and response status.
There is evidence now that Lyrica improves the post exercise response at the molecular level ... for responders. It makes nonresponders worse. This was done on patients with both fibro and CFS, as well as fibro patients. Due to the grant limitations this was not done on CFS or ME only patients. (I think this was money from Pfizer?)
He pointed out that the Rituximab link to autoantibodies might be overstated a little, yet he does think a large subset may have autoantibody problems related to the vascular system.
There may be a blend of gain of function and loss of function autoantibodies in some patients.
Treatments exist now, but not a cure. Cures are being worked on (and I think this includes Rituximab).
In any case its clear there is a large percentage who seem to have something else wrong with them. In other words these studies are looking at a mix of patients with different things wrong.
All it takes to create major central fatigue, and autonomic dysfunction, is a loss of regulation of blood vessels in active muscle. If fatigue signalling metabolites rise and persist they can induced chronic changes in the brain response. Those metabolites arise in muscle though, particularly post activity.
While the mitochondrial appear to be impacted its likely that only some have mitochondrial disease, the rest appear to have secondary mitochondrial dysfunction induced by the disease itself.
There is another double blinded autoantibody study in progress.
Streptococcus A epitope similarity to some of these receptors has been noted, and these problems often arise after a strep infection.
There is evidence now that Lyrica improves the post exercise response at the molecular level ... for responders. It makes nonresponders worse. This was done on patients with both fibro and CFS, as well as fibro patients. Due to the grant limitations this was not done on CFS or ME only patients. (I think this was money from Pfizer?)
He pointed out that the Rituximab link to autoantibodies might be overstated a little, yet he does think a large subset may have autoantibody problems related to the vascular system.
There may be a blend of gain of function and loss of function autoantibodies in some patients.
Treatments exist now, but not a cure. Cures are being worked on (and I think this includes Rituximab).
In any case its clear there is a large percentage who seem to have something else wrong with them. In other words these studies are looking at a mix of patients with different things wrong.
All it takes to create major central fatigue, and autonomic dysfunction, is a loss of regulation of blood vessels in active muscle. If fatigue signalling metabolites rise and persist they can induced chronic changes in the brain response. Those metabolites arise in muscle though, particularly post activity.
While the mitochondrial appear to be impacted its likely that only some have mitochondrial disease, the rest appear to have secondary mitochondrial dysfunction induced by the disease itself.
There is another double blinded autoantibody study in progress.
Streptococcus A epitope similarity to some of these receptors has been noted, and these problems often arise after a strep infection.
alex3619
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Thursday Nov 19, 10 am Pacific Standard Time? I took notes during the video but I do not know if I got it right, I was too busy listening.
Forbin
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As someone who became ill following a "flu" featuring a uniquely agonizing sore throat (searing pain every time I swallowed), I find this StrepA molecular mimicry theory pretty interesting.
I never saw a doctor, so I can't swear I had strep. My sore throat went away without treatment in a few days, which apparently can also be the case with untreated strep (although untreated strep can also lead to serious complications). If you have strep, you are contagious as long as you are symptomatic, which is another reason to get treated with antibiotics.
Interestingly, following my "sore throat," there was then a lull of a couple of weeks before ME hit me out of the blue. Likewise, there can also be a lull of weeks between strep throat and the onset of rheumatic fever. Apparently, you can get rheumatic fever up to 4 or 5 weeks after your strep throat resolves, when you are feeling fine.
It does make one wonder...
I never saw a doctor, so I can't swear I had strep. My sore throat went away without treatment in a few days, which apparently can also be the case with untreated strep (although untreated strep can also lead to serious complications). If you have strep, you are contagious as long as you are symptomatic, which is another reason to get treated with antibiotics.
Interestingly, following my "sore throat," there was then a lull of a couple of weeks before ME hit me out of the blue. Likewise, there can also be a lull of weeks between strep throat and the onset of rheumatic fever. Apparently, you can get rheumatic fever up to 4 or 5 weeks after your strep throat resolves, when you are feeling fine.
It does make one wonder...
alex3619
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This is consistent with an autoimmune response, but does not prove it.
lansbergen
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He, he. At last
It was an excellent webinar. He spent quite a while talking about recent research from three other groups (including from the Rituximab study) which had shown abnormal auto-antibody levels in ME/CFS patients related to controls. Both adrenergic alpha and beta receptors were implicated in all 3, with extremely little overlap - basically 1 control was a little higher than the rest in one study, and then was at the same level as 1 patient that was a bit lower than the rest.
He had a pretty good theoretical explanation of how autoantibodies to those receptors could cause (some?) ME/CFS symptoms by screwing with circulation, and his explanation of POTS symptoms made a lot of sense, even when it's not triggered by other BP issues. Basically the rapid heart beat means that the heart doesn't have time to fill between beats, so each beat isn't pumping enough blood. And that's why people with POTS feel like crap, even if their orthostatic intolerance comes with high blood pressure instead of low blood pressure. Though he did emphasize that there are definitely other types of OI.
So those circulatory problems can result in metabolic waste accumulating, because it isn't getting removed efficiently enough. That waste triggers the neurological reaction of fatigue, and because the waste still isn't getting cleared efficiently, the fatigue continues instead of wearing off quickly like it does for healthy folks. I think I would've liked more detail regarding this bit, and an explanation of how it might cause swollen lymph nodes and such.
Dr Light then tied all of that into his previous work showing altered expression of the adrenergic alpha 2A receptor in ME patients following exertion, compared to controls. And from there he went into some newer placebo-controlled research regarding Lyrica in ME/CFS + FM and pure FM patients versus controls.
Basically about half of the FM patients on placebo, with or without CFS, had expression of about 6 genes before and after exertion (several time points) which was radically different to healthy controls. In those patients, Lyrica then largely (but not completely) normalized gene expression. In the other half when on placebo, they started with gene expression closer to the healthy controls, and Lyrica made things quite a bit worse.
So they potentially identified responders and non-responders to Lyrica, and their report of improved or worsened symptoms on Lyrica corresponded with their gene expression when on Lyrica. So basically if Lyrica made them feel awful, it was because Lyrica was altering things in a pretty unhelpful manner.
He had a pretty good theoretical explanation of how autoantibodies to those receptors could cause (some?) ME/CFS symptoms by screwing with circulation, and his explanation of POTS symptoms made a lot of sense, even when it's not triggered by other BP issues. Basically the rapid heart beat means that the heart doesn't have time to fill between beats, so each beat isn't pumping enough blood. And that's why people with POTS feel like crap, even if their orthostatic intolerance comes with high blood pressure instead of low blood pressure. Though he did emphasize that there are definitely other types of OI.
So those circulatory problems can result in metabolic waste accumulating, because it isn't getting removed efficiently enough. That waste triggers the neurological reaction of fatigue, and because the waste still isn't getting cleared efficiently, the fatigue continues instead of wearing off quickly like it does for healthy folks. I think I would've liked more detail regarding this bit, and an explanation of how it might cause swollen lymph nodes and such.
Dr Light then tied all of that into his previous work showing altered expression of the adrenergic alpha 2A receptor in ME patients following exertion, compared to controls. And from there he went into some newer placebo-controlled research regarding Lyrica in ME/CFS + FM and pure FM patients versus controls.
Basically about half of the FM patients on placebo, with or without CFS, had expression of about 6 genes before and after exertion (several time points) which was radically different to healthy controls. In those patients, Lyrica then largely (but not completely) normalized gene expression. In the other half when on placebo, they started with gene expression closer to the healthy controls, and Lyrica made things quite a bit worse.
So they potentially identified responders and non-responders to Lyrica, and their report of improved or worsened symptoms on Lyrica corresponded with their gene expression when on Lyrica. So basically if Lyrica made them feel awful, it was because Lyrica was altering things in a pretty unhelpful manner.
Do you find all biomedical research offensive, or just the research which disagrees with your personal feelings about the cause of ME/CFS? It was an excellent presentation, regardless of what anyone's beliefs are regarding pathology, and certainly not a waste of anything.
Forbin
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Jonathan Edwards
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Rheumatic fever is not autoimmunity as far as we know. This is a common misconception.
I will look at the webinar this morning.
Excellent presentation. I expect he will draw a lot of flak here for his discussion of strep A & beta adrenergic receptor molecular mimicry hypothesis. The subgroup he was discussing is certainly in line with my history, though. My illness started after a series of strep infections. POTS sudden onset followed about a decade later after an undiagnosed sore throat illness.
I would just add that these findings re: pregabalin & gabapentin are interesting. Dr Goldstein regarded gabapentin (Neurontin) as one of his top drugs for CFS/FM patients. This study by Light et al nicely validates those clinical observations using a double-blind crossover design and gene expression measurements. It also explains why some with this diagnosis feel worse / absolutely awful on this treatment.
I would just add that these findings re: pregabalin & gabapentin are interesting. Dr Goldstein regarded gabapentin (Neurontin) as one of his top drugs for CFS/FM patients. This study by Light et al nicely validates those clinical observations using a double-blind crossover design and gene expression measurements. It also explains why some with this diagnosis feel worse / absolutely awful on this treatment.
I'm currently on Pregabalin for sleep at a much lower dose than used in the study and have been on it for years. I'm now trying to come off it, and have become concerned by the effects of the long-term use of what is basically a neuropsychiatric medication on the brain. I'd be worried about taking the monster doses that he's talking about in the long-term, but I don't know if my concern is well-founded. I don't have the expertise (or concentration, or ability to read screeds of stuff) to assess the risk.
bertiedog
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I have only ever taken 25 mg Lyrica given to me as a possible migraine preventative. It sent me to sleep for 30 minutes and I was very fatigued and a bit dizzy after so for the life of me I cannot imagine how anybody would ever get up to 150 mg a dose and higher!
Like many people with ME/CFS I am very sensitive to medication whereas I have noticed that most of the people who have Fibromyalgia in the group that I run locally are able to take huge doses of medication so there does seem to be differences between the 2 groups. Our group consists of around 80 people and I have come into contact with well over 300 people over the years who suffer with FM and this ability to tolerate pretty strong medication seems to be the rule and not the exception.
Pam
Yeah. I've seen some patients with FM and bipolar disorder on like 600 mg of Lyrica. I think that intolerance of normal doses of a wide range of medications is one distinguishing characteristic of ME/CFS vs. other stuff.
Jonathan Edwards
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I realise that this is a webinar for a patient audience but the immunology side is really not very good - it includes some factual errors and oversimplified interpretations.
Two issues are probably worth flagging up specifically. One is the molecular mimicry and the other the POTS physiology.
I am very sceptical about invoking molecular mimicry to streptococci. This idea was put forward around 1960 as the explanation for rheumatic fever but in the subsequent 50 years never validated even for that disease. It seems to me inherently unlikely that the same old theory from 1960 is going to explain things every time somebody looks at a new immune disease. Light talks of an 85% homology in an epitope. I do not think that is even suggestive of something significant. A single amino acid change will change the shape of a peptide and antibodies recognise peptides in their quaternary conformations in whole proteins, so that the amino acid sequence is only a part of the story anyway. I am pretty sure you could find this level of similarity in any biological material picked at random.
And as I have said many times before if you follow through what you would expect to happen with similarity of epitopes you don't actually end up with an explanation for why a mistake is made. Nor does rheumatic fever behave like an autoimmune disease. In modern immunological terms none of it hangs together I am afraid. I have no idea why people are still taking it seriously.
I am now puzzled about POTS. As Valentijn has summarised he said:
To me that cannot be right, although I am prepared to learn otherwise. The function of the heart is to pump blood and it achieves that by creating a head of pressure in the aortic root which forces blood through the circulation. So if the heart is beating too fast to pump effectively (which certainly can occur in tachycardia over 200/min) then by definition it will not be generating an adequate pressure in the arterial tree. But in POTS it is said that the pressure is normal or high. That means that the problem is NOT inadequate pumping by the heart. Things might be complicated by peripheral constriction maintaining blood pressure but in that case it would be the arterial constriction that was starving the tissues of blood, not the poor heart pumping. By definition if the arterial pressure is normal or high the heart is doing all it should be expected to do.
Can anyone explain why that is not the case?
That might have been due to time limitations ... he had 45 minutes to cover a lot of ground, and OI was a bit peripheral.