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

Jonathan Edwards said:
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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Perhaps this is a better question for another thread, but isn't CD38 expressed on NK cells and also induced in macrophages/monocytes? What reason is there to believe that any response to daratumumab, if it is a real effect, is mediated by B cell depletion rather than simply NK cell depletion? In which case low baseline NK numbers in non-responders simply indicate that their disease is not NK-driven.
 
jnmaciuch said:
What reason is there to believe that any response to daratumumab, if it is a real effect, is mediated by B cell depletion rather than simply NK cell depletion? In which case low baseline NK numbers in non-responders simply indicate that their disease is not NK-driven.
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When I said the basis of the daratumumab work I was implying the motivation, so questions like these are askable and I am sure Oystein Fluge would be the first to consider them legitimate.

But we don't really have any reason to believe that removing NK cells would make people better. All NK cells are probably much the same so it seems unlikely that people have ME/CFS because they have bad NK cells. Bad B cells on the other hand we know all about. Moreover, the story for ME/CFS has always been that there aren't enough NK cells to start with, or that they aren't working well. That may be wrong but I am not sure I can think of a good reason why NK cells should be doing bad things unless of course they are mediating ADCC by picking up bad antibody! OK, killing the NK cell might in that situation do more than killing the wrong plasma cells but it is a bit unparsimonious a theory. It also takes us back to the same idea - that there are bad antibodies involved.

And of course the ones who don't respond seem to already have low NK cells - so why didn't they do even better? And if CD38 has a big impact on NK cells how does it manage to mediate ADCC against plasma cells? For these monoclonals the killing mechanisms are multiple but I think you end up arguing some fairly contradictory proposals.
 
 
Jonathan Edwards said:
There are all sorts of angles on this but in simple terms the data suggest that the problem may be with lymphocytes signalling to nerves (and maybe nerves signalling back to lymphocytes) without that being mediated by any inflammatory or damaging process outside lymphoid tissue itself. If the signalling is mostly mediated by cell surface ligand or local cytokine interaction nothing my be visible on standard tests.
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Thanks, very interesting! That would definitely explain some of the puzzling things about ME/CFS.

Jonathan Edwards said:
Nobody knows why Stephane Grappelli was so good at playing the violin.
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He could really play, couldn't he!

I'm a guitarist and while I was no Django Rheinhart my main area of talent was improvising lead guitar. When I had mild ME I often found that when I was jamming I had a phenomenon I now recognise as 'hitting the wall' in terms of my capacity where my body had reached it's limit and was running on reserve (and pushing through would trigger PEM). What I would notice in those moments is that often I would sort of lose my ability to improvise fluently and articulate the notes and phrases I wanted in the way I intended, and it did feel like it was happening on the level of nerves, of sort of sense and muscle response. Its hard to put into words but it went beyond just being tired and making mistakes, it was like I got markedly shitter at the guitar!

Now this phenomenon happens very quickly and to a much greater degree if I pick up the guitar for a few minutes and put on a backing track. If I push it I can still muddle through for a short while (and then pay for it) but there is definitely something going on with the nerves/muscles beyond mental fatigue and muscle power loss.
 
hotblack said:
Some papers which came up in a search, the first had general background on HLA-C which I found interesting,
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That first review looks to be written by people who may not be experts, but just review writers (tends to be the case for Frontiers). Some of the interpretation of mechanism looks a bit simplistic. It is nevertheless quite informative. I note that they mention a protective allele of HLA-C for Graves disease. That is interesting because Graves is a classic antibody-related autoimmune disease and this is Class I, not Class II and Class I is not supposed to be directly involved in antibody production. There also seem to be HLA-C binding receptor alleles relevant to lupus. So maybe HLA-C comes in where you have antibody involved but also some background aberrant interaction with CD8 cells or NK cells. Interestingly, the paper I have been writing with Jo Cambridge and Jackie Cliff is all about trying to se how one might get a 'hybrid' situation in ME/CFS.

I am quite sure this is all going to make sense pretty rapidly. We just need the DecodeME data to see how that matches up! Chris Ponting is doing his very best to get his data out, I know.
 
Jonathan Edwards said:
Some of the interpretation of mechanism looks a bit simplistic.
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That’s probably why it appealed to me :)

Jonathan Edwards said:
Interestingly, the paper I have been writing with Jo Cambridge and Jackie Cliff is all about trying to se how one might get a 'hybrid' situation in ME/CFS.

I am quite sure this is all going to make sense pretty rapidly. We just need the DecodeME data to see how that matches up! Chris Ponting is doing his very best to get his data out, I know.
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I think we’re all looking forward to your, Jo and Jackie’s paper, the DecodeME results and the influx of neurobiologists!

Until then we can amuse ourselves learning things and prodding and pulling at other things.
 
I am wondering what people make of the genes relating to NA transcription. My simplistic thought is that maybe rare gene alleles that are a bit duff on DNA transcription may make you more susceptible to just about any disease that involves regulation. But maybe there is more to it.

I wonder if these genes have been looked at in a range of other chronic diseases that look like regulatory errors. And in diseases that look like something else. I also wonder if this is more of a problem with a rare gene allele search than for a GWAS and that this weighting to DNA transcription may not show up on GWAS.
 
Jonathan Edwards said:
I am wondering what people make of the genes relating to NA transcription. My simplistic thought is that maybe rare gene alleles that are a bit duff on DNA transcription may make you more susceptible to just about any disease that involves regulation. But maybe there is more to it.

I wonder if these genes have been looked at in a range of other chronic diseases that look like regulatory errors. And in diseases that look like something else. I also wonder if this is more of a problem with a rare gene allele search than for a GWAS and that this weighting to DNA transcription may not show up on GWAS.
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Are you talking about the epigenetic regulators (HDAC, DMNT) or other genes? I've been going down the rabbit hole on the epigenetic side
 
jnmaciuch said:
Are you talking about the epigenetic regulators (HDAC, DMNT) or other genes? I've been going down the rabbit hole on the epigenetic side
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Those will do. Some of the others come up on the gene spec as involved in transcription but the info is very brief.

Important not to eat honey if you go down a rabbit hole. It is hard to get out, according to a certain bear.
 
Turtle said:
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?
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The ISS has developed a unique microbial environment —

Adaptation to space conditions of novel bacterial species isolated from the International Space Station revealed by functional gene annotations and comparative genome analysis (2024, Microbiome)

And spaceflight alters the microbiome that the astronauts bring with them —

The human microbiome in space: parallels between Earth-based dysbiosis, implications for long-duration spaceflight, and possible mitigation strategies (2024, Clinical Microbiology Reviews)

Reanalysis of the Mars500 experiment reveals common gut microbiome alterations in astronauts induced by long-duration confinement (2021, Computational and Structural Biotechnology Journal)

Spaceflight alters host-gut microbiota interactions (2024, Nature npj Biofilms and Microbiomes)

Longitudinal multi-omics analysis of host microbiome architecture and immune responses during short-term spaceflight (2024, Nature Microbiology)

Cardiovascular changes under the microgravity environment and the gut microbiome (2024, Life Sciences in Space Research)

Human gut microbiome and metabolite dynamics under simulated microgravity (2023, Gut Microbes)

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight (2019, Science)

Preparing for the crewed Mars journey: microbiota dynamics in the confined Mars500 habitat during simulated Mars flight and landing (2017, Microbiome)

Understanding the Complexities and Changes of the Astronaut Microbiome for Successful Long-Duration Space Missions (2022, Life)

Spaceflight Virology: What Do We Know about Viral Threats in the Spaceflight Environment? (2022, Astrobiology)
 
Jonathan Edwards said:
Those will do. Some of the others come up on the gene spec as involved in transcription but the info is very brief.
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Ah I see from your earlier post that you're probably referring to NME1/2/3. In my searches they came up specifically as transcription factors, particularly for MYC.

The interesting thing about all the DNA related hits is that loss of function mutations in them are very strongly associated with several cancers, to the point that it seems shocking for someone with these mutations to not develop cancer. So for these particular cohorts, the individuals with those mutations either have a cancer comorbidity that was not evaluated in this study, or the more interesting possibility: that something about ME/CFS is protective against those cancers.

The only reason I entertain that latter possibility is because of the particular rabbit hole I've been down. For the epigenetic regulators, I've been looking into immunological responses to viral infection that are mediated by those epigenetic modifications. As an example, activation of interferon gamma production is known to be regulated by histone acetylation. And knocking out interferon receptors seems to predispose mice to many types of cancer (I believe this was early evidence for constitutive interferon production in the tissue despite considerable difficulty detecting it).

So the question is: what epigenetic marks are switched on during viral infection that ought to be turned off once the pathogen is cleared? A loss of function mutation in HDAC, for example, would certainly cause problems in that scenario, as would other less deleterious mutations that act on the pathway normally leading to deacetylation of IFNG. And interferon gamma is one strong possibility, though certainly not the only one.

For what it's worth, MYC is also known to be a negative regulator of type I interferons in pDCs.

Interested to hear if you have any thoughts on this--I can come up with tons of ideas, but don't quite have the expertise to shred them apart until one sticks.

Jonathan Edwards said:
Important not to eat honey if you go down a rabbit hole. It is hard to get out, according to a certain bear.
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Luckily I have a remarkable ability to find new rabbit holes to get me out of current rabbit holes. I suppose the laymen just call it "being easily distracted."
 
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jnmaciuch said:
Luckily I have a remarkable ability to find new rabbit holes to get me out of current rabbit holes. I suppose the laymen just call it "being easily distracted."
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Hah! The attraction of the rabbit hole isn’t the honey but the fact that’s is a rabbit hole!

As for the cancer connection - I just hope that it makes it easier to make a case for pharma to get involved at some point.
 
jnmaciuch said:
Interested to hear if you have any thoughts on this--I can come up with tons of ideas, but don't quite have the expertise to shred them apart until one sticks.
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Yes, well, when I read your second paragraph I immediately thought 'that's going to be gamma interferon'. So either there is some telepathy going on or this might actually fall into place rather quickly.

I have some information you can't have, which is infuriating, but unavoidable.
I think this is going to get sorted. I may be a bit old and out of touch to make much of a contribution but I am confident we have the minds we need and batting it around is the way to maximise chances of getting there quickly.

It seems as if there are some volume controls that involve medium term epigenetic steps linking in to volume of signals like interferons. I would go for gamma but they may all share some transcriptional regulation I guess. We need some sort of widget to stop the spring loading flipping back into homeostatic control mode but rearrangements of B or T cell receptors would do that and with at least a hint of an MHC signal I think that might pan out. On the other hand the epigenetics could really take over the show and provide the widget as well, as Humer suggests.

That still leaves my query open as to whether you might get genes like this coming up with any old disease involving regulation but it may not matter that much.
 
Utsikt said:
Exciting! Any estimates for a timeline?
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Hard to say. Unfortunately solveME is restructuring their grant program and told me they won’t be accepting applications, possibly it’ll reopen later this year. I’m also looking into pilot grants from my institution, which might be enough to cover a small cohort. It might take a few tries to get an award with an absence of any preliminary data, though.

Realistically, no sooner than a year, probably longer. Which is disappointing, but I’m doing everything I can to move it along.
 
jnmaciuch said:
Hard to say. Unfortunately solveME is restructuring their grant program and told me they won’t be accepting applications, possibly it’ll reopen later this year. I’m also looking into pilot grants from my institution, which might be enough to cover a small cohort. It might take a few tries to get an award with an absence of any preliminary data, though.

Realistically, no sooner than a year, probably longer. Which is disappointing, but I’m doing everything I can to move it along.
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Did you see the recent biobank announcement?
 
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