Preprint Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+

duncan said:
Perhaps pretty much any agent can set things into motion, but it's old entrenched latent viruses that emerge to do the heavy lifting? I'm unclear how accurate testing for the latter really is, so how would we know?
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Testing for the latter wouldn't help. We probably all have latent herpes viruses in us so testing for the virus would tell us nothing. To know what is going on we have to work out the mechanism. Which takes me back to post #252.
 
Jonathan Edwards said:
I don't see a lot of difference.
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But we do see notable differences. Swollen lymph nodes, cognitive vs physical PEM, sore throats vs nada, swollen joints vs painful joints with no swelling....You get the idea. Perhaps these relatively minor differences boil down to different agents - assuming the major qualifying ME characteristics remain.
 
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Jonathan Edwards said:
Testing for the latter wouldn't help. We probably all have latent herpes viruses in us so testing for the virus would tell us nothing. To know what is going on we have to work out the mechanism. Which takes me back to post #252.
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Right. But maybe knowing could help? I mean, I agree, unraveling the mechanism is the grail. Still, wouldn't you want to know? What if it's a tandem? Somewhere along discovery, there may be import to knowing which microbes that extends beyond the pragmatic.
 
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Jonathan Edwards said:
In the suggested scheme no one microbe 'is responsible'. The latent one is the real problem. The trigger one might be any old microbe, so isn't very interesting.
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The tandem could matter. The combination could. Eh, I'm just musing. Some like me believe it may some day lead to accountability.

But revealing the problem, shining a light on the mechanisms, easily takes precedence.
 
duncan said:
But we do see notable differences. Swollen lymph nodes, cognitive vs physical PEM, sore throats vs nada, swollen joints vs painful joints with no swelling....You get the idea.
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I am not aware of ME/CFS involving swollen joints. I have never heard of it before and if it was a real association I think I would. People have swollen joints for all sorts of reasons quite commonly so I suspect it is a coincidence. Of course there are swollen joints in Lyme arthropathy but I don't see that as having anything to do with ME/CFS. Otherwise the features of ME/CFS are much the same for everyone I suspect. Latent HSV1, EBV and varicella/zoster give completely different pictures.
 
Braganca said:
@Jonathan Edwards Question from a non scientist — how does this synapses concept tie in to the itaconate trap theory (or any new itaconate related theory from other thread), if at all?
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The itaconate shunt is a way of explaining why innate immune cells might go on sending out danger signals when there is no danger any more. We need a story of that sort because it does seem as if some immune cells, possibly innate ones, are doing this. Phair suggested that this might happen in brain and brain fog might be due to ammonia build up. I doubt that but genetic variants for synaptic housekeeping might affect how well the brain could cope with that. I am more inclined to think that the innate immune signalling is going on in the lymphoid system, outside the brain, and that the synaptic housekeeping problem affects the way the brain copes with a continuing input of inappropriate signals.

All these stories have something to contribute to the debate, I think. We can argue through what each one predicts and see if it fits better than another. But now at least I think we have some idea where to be looking.
 
Jonathan Edwards said:
The itaconate shunt is a way of explaining why innate immune cells might go on sending out danger signals when there is no danger any more. We need a story of that sort because it does seem as if some immune cells, possibly innate ones, are doing this. Phair suggested that this might happen in brain and brain fog might be due to ammonia build up. I doubt that but genetic variants for synaptic housekeeping might affect how well the brain could cope with that. I am more inclined to think that the innate immune signalling is going on in the lymphoid system, outside the brain, and that the synaptic housekeeping problem affects the way the brain copes with a continuing input of inappropriate signals.
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I hope somebody is planning a cartoon version of all this.
 
Jonathan Edwards said:
I am not aware of ME/CFS involving swollen joints.
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You'd find quite a lot in the US.

Jonathan Edwards said:
Of course there are swollen joints in Lyme
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Sometimes. Sometimes not. Actually, frequently not.

Jonathan Edwards said:
I have never heard of it before and if it was a real association I think I would
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And yet I have, again perhaps due to proximity, perhaps due to length of time living it.

Jonathan Edwards said:
Otherwise the features of ME/CFS are much the same for everyone I suspect
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Clearly there can be overt differences outside of the defining characteristics, and even these can vary. And quite frequently do as so many conversations on this forum attest.

Jonathan Edwards said:
I don't see that anyone could have known enough to be accountable. It is not like tobacco manufacturers knowing since 1960 that their products were the main cause of lung cancer.
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Some believe there are such individuals. It may be very similar to those tobacco vendors after all.
 
I can understand why some want accountability.

For me it’s a waste of energy for something which will get little to nothing in return. My choice is to focus on the present and the future, try to improve things for as many people as possible. That’s still going to be a lot of work but feels like where we can make the biggest change and get the best bang for the buck.

I accept others feel differently.
 
duncan said:
But we do see notable differences. Swollen lymph nodes, cognitive vs physical PEM, sore throats vs nada, swollen joints vs painful joints with no swelling....You get the idea. Perhaps these relatively minor differences boil down to different agents - assuming the major qualifying ME characteristics remain.
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All variations which could just as likely a reflection of severity and the complex pathways involved, with different bits switching on/off or interacting up or downstream. I think we discussed this more in another thread recently but forget where.

The differences don’t seem to me any greater than seen in other conditions. Look at PD or MS. While there are so many commonalities between us, something I’ve found again and again sharing experiences on these forums.
 
hotblack said:
All variations which could just as likely a reflection of severity and the complex pathways involved, with different bits switching on/off or interacting up or downstream.
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Agreed, they could be. What leans me toward a different possibility is what to some seems like deliberate mischarcterizations that have been haunting diseases such as ME for half a century - and obviously not just from the BPS crowd. But clearly you have a point.

hotblack said:
For me it’s a waste of energy for something which will get little to nothing in return.
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Nod. Understood. I spent my adult life in research, where sometimes just learning, just knowing, was the goal. I'd like to say that was all that was in play for me, but that wouldn't be accurate. Accountability, if possible and if appropriate, when we are talking about literally millions and millions of victims - and those numbers grow daily - is not unreasonable, even if we are only talking about bringing truths to light.

Still, I share your sense of priority.
 
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duncan said:
Nod. Understood. I spent my adult life in research, where sometimes just learning, just knowing, was the goal. I'd like to say that was all that was in play for me, but that wouldn't be accurate.
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Yeah I absolutely understand both those feelings. I share that, perhaps intellectual curiosity, to get to the bottom of things and really fully understand. And have definitely felt a need for accountability and justice at many times. I’d be surprised if there’s anyone affected who hasn’t. I’m not sure what or why it is but that has shifted as time has gone on, maybe not entirely but largely.

I’m going a bit off topic here but it’s been interesting, thanks @duncan
 
Jonathan Edwards said:
In the suggested scheme no one microbe 'is responsible'. The latent one is the real problem. The trigger one might be any old microbe, so isn't very interesting.
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NASA research seems to conclude that astronauts have recurrring virus activation after 10-14 days after they arrive at ISS? Not even a microbe needed?
They travel airtight and arrive airtight. No new microbe that can cause their own latent virus to come up again?
A very delayed PEM? Exercise induced tissue damage that releases old viruses?
 
hotblack said:
I’m going to try a definition since this has been coming up a lot recently…

Linkage disequilibrium is when at a population scale different segments of DNA, different genetic variations, occur together in different places more or less frequently than you would expect by chance.

About right?
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Jonathan Edwards said:
Yes. Every generation DNA is supposed to be randomly chopped up and exchanged between sister chromosome threads. Which should mean that if a great-great-great-grandmother has HLA A3, B6,C2,DR2 genes in line on a chromosome that set will gradually get separated and re-assorted with each generation. The process is slow so in populations you see genes being passed down in sets for many generations but over millions of years the sets could be randomly re-sorted.

'Linkage disequilibrium' is sometimes used to mean slightly different concepts but here I understand it to mean that for some reason a set of genes doesn't get split up as often as expected, or, often assumed, that it may get split up but there is a significant survival difference in chromosomes with the original set and those with the set split up. So you may end up with a population where A3,B6,C2 and DR2 keep showing up as a set even over millions of years presumably because this is a really good set to have.

Up until now linkage disequilibrium has mostly been seen as a nuisance in genetic studies - it means that it may be difficult to pin down which gene is really related to a disease. But linkage disequilibrium is itself of biological interest. It should be telling us something but often nobody is quite sure what.
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Just to add to what @Jonathan Edwards already explained, we expect a certain amount of linkage disequilibrium simply due to distance on the chromosome.

That “shuffling” happens by the two arms of the sister chromatids crossing and then swapping places, so two genes that are next to eachother on the chromosome are less likely to randomly have a cross point form between them and end up shuffled away from each other.

However, there are frequently haplotypes (sets of alleles) that appear together more frequently than you would expect based on their distance. This is likely due to some benefit in that set of alleles as Jonathan alluded to, and we don’t understand all the mechanisms of that yet.

It's a nuisance in genomic studies because when this happens, it becomes tricky to determine whether the certain alleles for gene A or gene B or maybe the combination of alleles is responsible for association with phenotype.

In rare variant studies, its less of a concern simply because the specific alleles are not distributed in the population (likely because they are quite deleterious), so you don't get enough frequency to see patterns of tandem inheritance in the first place. It's more of a problem in GWAS that looks at highly variable genomic regions.
 
Sasha said:
Is the thinking about mechanism that's going on here consistent with the thinking that's going on in the daratumumab work?
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The basis of the daratumumab work is that antibodies, produced by B cells and their plasma cell offspring, are in some way involved. That would be consistent with gene links to immune mechanisms but we would expect the links to be to MHC Class II rather than Class I or innate immune markers. But things get complicated here. Fluge's group did find a Class II link with DQ. I don't think it replicated but there may be spurious reasons for that. The Zhang study picked up Class I in the form of HLA-C but there are linkages across Class I and Class II which may mean that confusing signals come up - very much as just mentioned. And at the end of the day the immune system functions as a complex whole so the link to HLA-C might fit in some way.

My hunch is that it may actually all fit together. The graph showing NK cell numbers being low in daratumumab 'non-responders' may be hard to interpret in terms of why but it gives quite an impressive sense that the daratumumab 'responses' really are biological effects, rather than placebo. There is no other good reason why the patients' cells should be so different.

I have admired the way Fluge has plugged on with B cell work despite negative signals. I have tended to think he may be over-optimistic about it since the ritux phase 3 but I am beginning to think he may be right after all.
 
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