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

The autoimmune diseases of AIR are chronic - lifelong. TB, if untreated is chronic, or at least until it leads to death.

Some treatments are aimed at primary causes, others at secondary pathway branches, so that is all very variable.

 

FWIW, this recent preprint also noted significant differences between severe and mild/moderate patients albeit with different markers.

https://www.s4me.info/threads/abnor...elitis-chronic-fatigue-syndrome-25-lee.42017/

 

To me uncertainty and partial information and things we as patients need to find ways to be comfortable with. If there’s anything we know about ME/CFS it is that it isn’t simple. I’m hugely hopeful about upcoming science, but expect that in even the most enlightening studies we’ll only uncover bits of a much larger picture at a time. A bit like the parable of the blind men and the elephant https://en.m.wikipedia.org/wiki/Blind_men_and_an_elephant

 

Agree about uncertainty from a practical perspective. From a subjective perspective it's much more tricky. Since I became severe, I have lost count of the amount of times I have asked 'what is happening to me?'.

I think we need to be clear on what exactly we are uncertain about to become comfortable with it. And asking questions/discussing the science here hopefully has some small benefit for the people doing the science.

Progress in the blind men and elephant fashion would be great and much better than our current situation. But in my heart I am hoping for one of the moments like Jonathan has described where everything suddenly fits together. Although we need to have some solid clues before that can occur.

 

Perhaps it’s time to start making split cohort analyses more common. And also time to stop studying a cohort of mild/moderate people and saying it applies to all pwME.

 

In theory the previous NICE Guidelines and the Cochrane Exercise review said that GET was only demonstrated for mild/moderate CFS, but in practice people approached all of ME/CFS with the idea that it could be treated by challenging people to do more. Hence the psychiatric units not bringing food to people with severe ME but forcing them to go to get it themselves or deliberately opening the curtains on individuals with light sensitivity.

 

I can confirm that from personal experience. In fact they ignore all your symptoms including medicine intolerances.

 

Does this have finding have implications for the plasma cells that derive from these B cells? Any chance they will be abnormal?

 

I don't think there is any reason to think the B or plasma cells are abnormal, just that the selection processes have been skewed. B and plasma cells in autoimmunity are entirely 'normal' as far as we know. (Except in rare cases where there may be an association with Monoclonal Gammopathy of Unknown Significance.)

 

On the thread that has now split from this one, we've been talking about the great difficulty, expense and time that would be involved in getting bone-marrow samples to follow this up.

But maybe another approach could be just to try out a treatment, if that's appropriate. If the finding was real, do we know what drug would be used to target the mechanism? And if that drug isn't toxic, would it be worth doing an exploratory trial of it as a way of indirectly confirming the biology?

 

No because we have absolutely no understanding of these B cell IgHV gene usage shifts. A likely candidate might be complement mediated selection but complement does so many things we would need to know much more and with much greater certainty to tart playing around with it.

 

In the Sato thread, I think there was some question of if their second cohort replicated the IGHV3-30 finding. Maybe this was before a revision that Jonathan says Jo Cambridge asked them to do.

But it does appear that this gene is high in cohort 2 as well. (Fig 5A)


And here is cohort 1. (Fig 1B)


But note that it's the same control group in both comparisons. Would be good to find the levels from another healthy control group in some other study to see if they look normal here.

 

Worth noting for any sort of speculation of why it might not apply to severe people, that the difference really isn’t clear cut, it looks like the vast majority of ME patients have it in normal range, but on average they are a little bit higher, with a few outliers that are much higher, than healthy controls.

 

True, but if it's some sort of compensatory mechanism you'd expect it to vary a lot in people with different activity patterns.

If it's found in other cohorts and we can come up with ideas about why the shift happens, it could tell us something important even if it's not causative.

 

We saw this using RNAseq so whatever small amount there was in that subset of B cells was enough to be quantifiable and different between admittedly small groups. What that means, I don't know, but just adding a bit of context regarding the small amount of material expected

Selection & maturation differences are something I really want to look at in more detail

 

I know relatively little about RNA technology but amounts of RNA would not necessarily have anything to do with the clonal commitment to a particular VH gene rearrangement would they?

A plasmablast in blood might presumably have a hundred times more RNA for that recombined Ig gene than a recently emerged naive B cell.

I guess that finding differential effects at any level are interesting but I am wary of people confusing gene expression with gene commitment.

 

Agreed and this is why I refrained from overanalysing in the paper absence of more detailed examination - reporting it and moving on seemed best until it is followed up

If we want to speculate here, some of the LC PBMC samples had IGHV3-30 mRNA at levels 60 times lower than some of the post COVID recovered PBMC samples. A change that dramatic in a mixed PBMC population would suggest to me more effector cells with that recombined gene - do you agree Jonathan?

What is also curious is that in our data IGHV3-30 mRNA levels are really high in PBMCs from asymptomatic people with ~3 months since infection yet extremely low in LC individuals at the same duration since infection. What do we know about circulating effector b cell lifespan/levels in LC? Have seen studies of this following severe infection but not LC specifically, I think?

In any case, speculation, need to follow up with typing assays and bigger sample size to nail this down. Maybe longitudinal data too. I'll leave it there, dont want to derail thread with too much speculation and off topic

 

Yes, it is certainly intriguing. And paradoxical effects might make a lot of sense if we are dealing with VH gene usage that functions normally as a sort of 'decoy'. Jo C and I had speculated about various predictions in the context of VH4-34 but it begins to look as if they might be relevant - but in relation to the other 'usual suspect' VH3-30. I know less about the behaviour of VH3-30 but it looks as if it may have a similar role in general B cell clonal regulation.

The population dynamics issue in peripheral blood threatens to make everything interpretable whichever way you like, which is problematic, but maybe there replication studies can show a consistency that means we can be more confident.

Interesting stuff.

 

Apparently there are reasons to think these antibodies are unlikely to be related to a specific antigen. But unlikely isn't zero, so just throwing out an idea for why the levels might be lower in more severe ME/CFS.

Maybe in healthy people, there's no pathogen so none of these antibodies.

In mild/moderate, there is a persistent pathogen, as well as a mild immune response keeping the infection somewhat at bay, detectable through these antibodies.

In severe, there is persistent pathogen, but no/little immune response, so no increased antibodies. And this could be why they are severe instead of mild: their body is doing less to fight off the pathogen, thus the pathogen can do more harm.