Rosetta Stone Study: £1.1m awarded to investigate links between ME/CFS and Long Covid

Jonathan Edwards said:
Well, you say countless findings. To which my brain replied "which... can't think of any much except maybe the fluorospot study and some of Jackie's work".
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I was referring to all of the findings that claim to have found some immunological difference or biomarker in LC.

And I think Altmann wanted to find the ones that stood up to scrutiny (which yes, I can only think of a few that would be worth looking at imo) and replicate them in ME/CFS. But you're right that it does sound very scattershot.
 
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Jonathan Edwards said:
Meaning that infection does not trigger autoimmunity much if at all. The meme is based on the 'molecular mimicry' theory which turns out to explain nothing. Epidemiology indicates that virtually all autoimmunity occurs at random without an external trigger.
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Most researchers I know interested in this are not looking into molecular mimicry so much as bystander activation, where viral infections provide a permissive environment helping to bypass peripheral tolerance in individuals already poised towards developing autoimmunity. So the formation of the initial autoreactive lymphocytes is random and the progression to full blown autoimmune disease is also a matter of chance, but it becomes more likely for an unfortunate chain of events to kick off when viral infections induce lymphocyte infiltration, high concentrations of immune signals that encourage activation, and lots of dead cell matter all in the same place.
 
Jonathan Edwards said:
Meaning that infection does not trigger autoimmunity much if at all. The meme is based on the 'molecular mimicry' theory which turns out to explain nothing. Epidemiology indicates that virtually all autoimmunity occurs at random without an external trigger.
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You think the recent studies showing that mononucleosis leads to MS have it wrong? Or that it means MS is not autoimmune?

Obviously most infections don't cause identifiable autoimmunity, as far as we know, or at least none that cause illness that we can detect, but a lot autoimmunity does seem to be triggered by infections. It's not as if the technology or resources needed to track this exist, but it still seems to be the main plausible mechanism.
 
jnmaciuch said:
Most researchers I know interested in this are not looking into molecular mimicry so much as bystander activation, where viral infections provide a permissive environment helping to bypass peripheral tolerance in individuals already poised towards developing autoimmunity. So the formation of the initial autoreactive lymphocytes is random and the progression to full blown autoimmune disease is also a matter of chance, but it becomes more likely for an unfortunate chain of events to kick off when viral infections induce lymphocyte infiltration, high concentrations of immune signals that encourage activation, and lots of dead cell matter all in the same place.
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That would make autoimmunity kind of similar to cancer, then? It can happen randomly, but it can also be amplified by series of events, which as far as our technology allows pretty much adds up to being random, or probabilistic anyway, since we can't realistically follow the whole chain of events, even in the most controlled settings we can come up with.
 
rvallee said:
That would make autoimmunity kind of similar to cancer, then? It can happen randomly, but it can also be amplified by series of events, which as far as our technology allows pretty much adds up to being random, or probabilistic anyway, since we can't realistically follow the whole chain of events, even in the most controlled settings we can come up with.
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That's the idea

rvallee said:
You think the recent studies showing that mononucleosis leads to MS have it wrong? Or that it means MS is not autoimmune?
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EBV would be somewhat of a different case since EBV directly infects the B cells that drive autoimmune disease. The recent studies didn't definitively prove that EBV is a culprit (in my opinion) but they do show some hints that latent EBV changes how B cells function in a way that makes the unfortunate-series-of-events more likely. So in principal it would be similar to the idea of lots of different viral infections potentially creating a permissive environment for things to go wrong, but EBV would be a much more direct hand on the trigger than something like COVID-19 (which would only be influencing the general environment of potentially autoreactive cells)
 
jnmaciuch said:
it becomes more likely for an unfortunate chain of events to kick off when viral infections induce lymphocyte infiltration, high concentrations of immune signals that encourage activation, and lots of dead cell matter all in the same place.
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OK but I never came across any evidence or motivation for that idea. I suspect they are still stuck in the old causal meme, even if they have realised that mimicry is useless.

The epidemiology just doesn't support it, except perhaps in a very few atypical cases.
 
rvallee said:
You think the recent studies showing that mononucleosis leads to MS have it wrong? Or that it means MS is not autoimmune?
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EBV is unique in this context as a permissive agent because it permanently alters B cell regulation.
rvallee said:
but a lot autoimmunity does seem to be triggered by infections
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Who says? I have heard that trotted out by immunology lecturers for half a century but the evidence is almost entirely against. Old myths die hard.
 
rvallee said:
That would make autoimmunity kind of similar to cancer, then? It can happen randomly, but it can also be amplified by series of events, which as far as our technology allows pretty much adds up to being random, or probabilistic anyway, since we can't realistically follow the whole chain of events, even in the most controlled settings we can come up with.
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It is very like cancer, as we pointed out in 1999. RA is more likely if you smoke, so toxic signals can alter the threshold, just as for cancer, although in cancer the toxins may be more closely linked to the mutations. In autoimmunity the mutations themselves are normal events. The one thing that does not seem to matter is infection, except perhaps EBV, but since almost all of us are infected that has been hard to reveal.
 
Jonathan Edwards said:
OK but I never came across any evidence or motivation for that idea
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I've seen presentations on the mouse work and I know translational studies are in the pipeline. If it's just a fluke from the animal models I'm sure we'll know soon enough. But as it stands it does seem a more plausible explanation for things like post-viral thyroiditis and T1D following influenza
 
jnmaciuch said:
I've seen presentations on the mouse work
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Mice are completely irrelevant here. You can build mouse models that do whatever you like in immunology. That has been going on since collagen II and adjuvant arthritis in the 1970s. You can prove that rheumatoid arthritis is due to regulatory B cells if you want to, and people have become Deans of Faculty on the back of it. Give me a break.
 
Jonathan Edwards said:
The epidemiology just doesn't support it, except perhaps in a very few atypical cases.
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I'm not sure that epidemiology would provide much evidence if some combination of predispositions are needed in the first place for infection to tip over peripheral tolerance mechanisms. The relevant comparisons would be taking people with similar genetics and seeing if people exposed to viral infections develop autoimmunity more frequently. Pandemics might show a small uptick, as has been suggested with Covid, but they also might not if the people predisposed to autoimmunity are getting a flu every few months anyways. You'd have to be extraordinarily creative and well resourced to find a big enough viral-naive control group to prove or disprove

Jonathan Edwards said:
Mice are completely irrelevant here. You can build mouse models that do whatever you like in immunology. That has been going on since collagen II and adjuvant arthritis in the 1970s. You can prove that rheumatoid arthritis is due to regulatory B cells if you want to, and people have become Deans of Faculty on the back of it. Give me a break.
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jnmaciuch said:
and I know translational studies are in the pipeline. If it's just a fluke from the animal models I'm sure we'll know soon enough.
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I don’t understand what’s being proposed in a bystander hypothesis.

Is it like a bystander casualty in a drive-by shooting? So the attacking immune cells miss and damage something else? If so, why would thay selectively miss and end up attacking certain kinds of tissue or molecules to create distinct pathologies, and not just randomness? And wouldn’t that just be mimicry with some extra steps?
 
jnmaciuch said:
I'm not sure that epidemiology would provide much evidence if some combination of predispositions are needed in the first place for infection to tip over peripheral tolerance mechanisms.
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I don't think it is that difficult. There are loads of major epidemiological differences in terms of infection prevalence, epidemics, age of onset that ought to have been picked up over the centuries. The default assumption from observing autoimmune disease is that it has nothing to do with any particular infection. It is just that immunologists are obsessed with the idea that it should. Because they don't even understand the stochastic aspect. They all give lectures saying diseases are a mixture of genes and environment.

The reality is that most immunologists have very little imagination. You are enough of an exception to see that!!
 
What is a translational study in a pipeline?

I am afraid I don't take much notice of hints about secrete science. I have always worked on the basis that good ideas are for sharing, now. People don't pinch good ideas by and large -
they have too little imagination.

The evidence on infection triggering human autoimmune disease is minimal. And the evidence against pervades clinical experience and epidemiological data. I don't think anyone needs to hold their breath to be honest.
 
Utsikt said:
I don’t understand what’s being proposed in a bystander hypothesis.
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Every person has a number of autoreactive lymphocytes that bypass central tolerance. A lymphocyte that recognizes any antigen has to pass through certain checkpoints in order to start causing a fuss, and that gets helped along by signaling molecules from other immune cells. In most people, there are sufficient mechanisms of peripheral tolerance that essentially counteract that transition for self-recognizing lymphocytes.

The idea of bystander activation is that during an infection, you have a perfect storm of many of those immune signals that help that transition along, so already existing autoreactive lymphocytes (which get called into sites of infection regardless of their antigen specificity) might be more likely to turn into activated problem-causing lymphocytes in the specific environment of an infection. I am probably oversimplifying several parts of people’s ideas but that’s the basic gist
 
Jonathan Edwards said:
The default assumption from observing autoimmune disease is that it has nothing to do with any particular infection.
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I think the point is that it’s not virus-specific at all, except for some cases of cell type specificity dictating where the infection takes root


Jonathan Edwards said:
The reality is that most immunologists have very little imagination. You are enough of an exception to see that!!
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Thanks? I’m not saying I think this is probably the correct answer but I’m open to the idea because the specifics of what is being proposed wouldn’t have already been falsified by existing data. It’s up to the people doing that work to prove it to me, but unlike you I don’t see cause to dismiss the idea out of hand
 
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