Deep Sequencing of BCR Heavy Chain Repertoires in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Ryback et al

V.R.T. said:
But how could severe ME have a different starter pathway if some people start off mild and stay that way for many years before becoming severe, and some lucky people who have been severe for many years recover to a moderate or mild level over time?
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When I say starter pathway I do not necessarily mean that would be early in the disease course in time terms. This is very complicated to explain but I think the answer to all your questions might be that the casual pathways of ME/CFS may, like rheumatoid arthritis, involve something like fifty steps, each of which may be mediated by alternative versions.

The extreme example of this perhaps is that the step in RA where small immune complexes form and can bind to receptors to activate inflammation can be mediated by potentially a million different antibody species. Some of these might all be pretty similar in how they bind to each other but others might be significantly different in hundreds of ways.

The trick is to find an overall model for the pathway network that you can make predictions from without knowing absolutely every detail - which is what we did for using rituximab.

There are big question marks about how cohorts get selected for studies and there is not doubt that the lack of a signal in severe cases is puzzling, but it isn't so odd to me that I would be sceptical about the validity of the findings on those grounds.
 
V.R.T. said:
I don't buy the idea that severe ME is a separate condition. Perhaps some people are more vulnerable to becoming severe somehow but the idea that it is caused by a wholly different disease process seems unlikely to me.
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I agree. As someone who has been to parts of Tibet closed to foreigners and has swam in the sea in Antarctica all with ME but also spent years only getting out of bed to go to the toilet or to eat cold baked beans from the can, getting showered once a month if lucky, though the difference between mild and severe seems unimaginably huge, my subjective experience is of one condition.

My experience has been of relapses and remissions (though with an overall deterioration over three decades) not of different conditions switching on and off. Though over time new symptoms have emerged there has been a continuity too.
 
Jonathan Edwards said:
When I say starter pathway I do not necessarily mean that would be early in the disease course in time terms. This is very complicated to explain but I think the answer to all your questions might be that the casual pathways of ME/CFS may, like rheumatoid arthritis, involve something like fifty steps, each of which may be mediated by alternative versions.

The extreme example of this perhaps is that the step in RA where small immune complexes form and can bind to receptors to activate inflammation can be mediated by potentially a million different antibody species. Some of these might all be pretty similar in how they bind to each other but others might be significantly different in hundreds of ways.

The trick is to find an overall model for the pathway network that you can make predictions from without knowing absolutely every detail - which is what we did for using rituximab.

There are big question marks about how cohorts get selected for studies and there is not doubt that the lack of a signal in severe cases is puzzling, but it isn't so odd to me that I would be sceptical about the validity of the findings on those grounds.
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So the 'step' of severe ME might involve a shifting out of the step where the HV3-30 is increased and into a different process with a different starter?

Like hypothetically if you go from moderate to severe then the disease process becomes different, but when you improve back to moderate you have shifted back into the step(s) of the process involving this finding?

Or are you saying that the steps are all there all the time but in severe the variable that produces increased hv3-30 is substituted by a different possibility in that particular step? Like your example of the different antibodies in the RA step?

I am quite cognitively severe so struggle with scientific concepts although I find it fascinating.

I was certainly not questioning the validity of the finding, just trying to puzzle out why it wouldnt be the same for severe. As someone severe I do sometimes worry that progress, if it comes, will leave us behind. Perhaps that is irrational but there it is.
 
V.R.T. said:
As someone severe I do sometimes worry that progress, if it comes, will leave us behind. Perhaps that is irrational but there it is.
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I imagine it's very noticeable how few studies genuinely include severely ill people.

Perhaps it could be justifiable on ethical grounds in some cases? For a small preliminary study, it might seem unreasonable to invite participants who'd bear a disproportionately high cost for taking part.

But researchers could be better at giving their reasons for setting up small studies that can't, for instance, visit people at home to take samples. At least it opens up chances for severely ill people to offer ideas for better inclusion, which could be used when they have something more promising to study.
 
V.R.T. said:
As someone severe I do sometimes worry that progress, if it comes, will leave us behind. Perhaps that is irrational but there it is.
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Yes. I just imagine the situation of having to travel to a clinic to get the treatment or whatever, when it is physically impossible for me.

Or not having the money to afford the copayment on the treatment etc.
 
The way I suppose I would probably think about it is a complex circuit with lots of different electrical pathways/tracks and switches and components. Or maybe even just the electrical system in a house. And depending upon which switches are enabled different lights switch on. And sometimes you need multiple switches in the right position for a light to come on.

So mild/moderate/severe can be the same disease, but with different bits switched on. It’s not a linear progression, it’s incredibly complex, because biology seems to make even complex electronics look simple.
 
Peter Trewhitt said:
though the difference between mild and severe seems unimaginably huge, my subjective experience is of one condition.
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I was mild for many years before becoming severe. To me, both mild and severe feel like the same disease. The profound sickness, the intolerance to stimuli, and the lack of energy I suffered from when I was mild were exactly the same as now, when I am severe, only the intensity is so much stronger now. The threshold for PEM was of course much higher when I was mild. And PEM was not as devastating.

There is something so specific about ME/CFS, whether mild or severe. It’s hard to put it in words, but a good way to describe it is : ”feeling poisoned”, ”like dying”, ”exhausted to the bone”.

It’s unlike anything I have experienced when I was healthy. The only experience that comes somewhat close to the sickness of ME/CFS, is what I felt when I had very low blood sugar a couple of times in my youth.
 
hotblack said:
The way I suppose I would probably think about it is a complex circuit with lots of different electrical pathways/tracks and switches and components. Or maybe even just the electrical system in a house. And depending upon which switches are enabled different lights switch on. And sometimes you need multiple switches in the right position for a light to come on.
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Probably have to add genetic susceptibility to that too, which is another layer of complication. Is your twin and earth fully up to spec, or was it made in some shonky factory where they economised on the PVC for the sleeves? :D

It's very hard to visualise, biology seems vastly variable and sometimes entirely random. Any species relying on the binary choices of human-made systems probably wouldn't get beyond the first few cell divisions, it'd be way too easy to wipe out.
 
Kitty said:
It's very hard to visualise, biology seems vastly variable and sometimes entirely random
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Absolutely. The more I learn about biology the more you can see it using fundamental chemistry and physics, not just the ‘simple’ stuff but including crazy quantum and probabilistic stuff. Amazing stuff. So much more for us to learn and (try to) understand.
 
Yann04 said:
Yes. I just imagine the situation of having to travel to a clinic to get the treatment or whatever, when it is physically impossible for me.

Or not having the money to afford the copayment on the treatment etc.
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Yes I can see that, although for a truly effective treatment that could significantly reduce or block PEM the tradeoff would likely be worth it.

I suppose my concern is them finding drug targets that severe people don't have. Or there being additional complexities with the severe state and research/medicine just shrugging and saying tough luck, because the financial payoff will be much less if the mild/mod 75% are already back in the workforce.

All that is hypothetical and likely just based on personal paranoias.

I do really hope that this finding pans out and is the start of real progress.

Is DecodeME likely to shed more light on the finding in this paper, does anyone know?
 
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Jonathan Edwards said:
When I say starter pathway I do not necessarily mean that would be early in the disease course in time terms. This is very complicated to explain but I think the answer to all your questions might be that the casual pathways of ME/CFS may, like rheumatoid arthritis, involve something like fifty steps, each of which may be mediated by alternative versions.

The extreme example of this perhaps is that the step in RA where small immune complexes form and can bind to receptors to activate inflammation can be mediated by potentially a million different antibody species. Some of these might all be pretty similar in how they bind to each other but others might be significantly different in hundreds of ways.

The trick is to find an overall model for the pathway network that you can make predictions from without knowing absolutely every detail - which is what we did for using rituximab.

There are big question marks about how cohorts get selected for studies and there is not doubt that the lack of a signal in severe cases is puzzling, but it isn't so odd to me that I would be sceptical about the validity of the findings on those grounds.
Click to expand...

Is it possible that the same cause can lead to different diseases and it depends on for example which system the cause hits in our body but also another way around that different causes can lead to the same disease?

For example we have a tree with 3 branches. These 3 branches start from the top of the tree. Each branch represent one disease. For example ME/CFS, SM, lyme disease.
The less we understand these diseases the more they look different - the further we are from the top of the tree on our branch, the less we understand for example ME/CFS and it looks more different from SM. But the more we are going with our understanding of ME/CFS to the top, it can look more similar to SM and if we could arrive with our knowledges to the top of the tree we would find that the cause of these diseases is the same, the cause can just hit another pathway in the body and it leads to the different diseases. So if we would be able to treat the fundamental cause we could treat all diseases from this tree. The less we understand the diseases from this tree the more different and less effective the treatment is. I didnt want to say that ME/CFS, SM, lyme disease are the same, it was just an example to explain better.

But how I said it can be also another way around. Different causes can lead to the same disease. The further we are on our branch from the top it looks more similar our ME/CFS. The more we understand our ME/CFS branch and we approach the top, the more different looks our ME/CFS branch from another one. And if we are on the top we see that each ME/CFS branch is quite different disease just with similar symptoms. And the more we understand the disease of each ME/CFS branch the less similar will be the treatment.

I am not sur if I explained it good with my bad english :-)
 
Jonathan Edwards said:
Different clinical presentations, yes. I probably wouldn't call them different diseases. The TB bacillus can produce renal abscess, pneumonia, meningitis and all sorts. A defect in the AIR gene can lead to a range of different autoimmune states.
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I think the diseases which you mentioned are mostly not chronic. Do you think that it´s also possible in chronic diseases or how you call it different clinical presentation?
Then would it be possible to treat them with the same treatment if we would find the cause?
 
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