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

This and factoring in PEM I think is important here

May I ask you to please elaborate on this concept of a decoy? (glad you went in this direction because it did strike me as paradoxical)

 

It comes from the data on VH4-34. VH4-34 committed cells seem normally to enter T cell areas but not follicles and never progress to generate plasma cell clones manufacturing bulk antibody. That is an oversimplification but the rough idea. In lupus there is a loosening of control over B cell selection and VH4-34 committed cells appear to be allowed to make antibody. VH4-34 also has the odd property of binding to self carbohydrates.

This has led to the idea that these VH4-34 has been positively selected for in evolution not because it binds to some useful pathogen antigens but because the VH4-34 committed cells in some way facilitate effective maturation of other B cells. They engage T cells despite never being destined to respond with clonal expansion. I don't think it is clear what they are doing but one idea is that they act as decoys to prevent the B cells or T cells getting the wrong idea. Another is that they are a bit like worker bees building homes for the queen's eggs and never producing offspring themselves. Jo and I have had lots of theories over the years.

VH3-30 is clearly different but it seems to crop up when the immune response is skewed in various ways. The idea would be that both are some how 'moderator' clones in some sense. Decoy may be a bit too specific.

 

Maybe for mild/moderate people the compensatory mechanism for whatever is going on elsewhere is working while in severe it’s not or has stopped or paused for some reason. Or it may not even be a distinction as clear as severity but just for different people with ME/CFS at different times or in reaction to different things.

So all people have have the underlying problem, maybe even at different severities or not, but in the numerous gates and interactions on the downstream path from this regulatory signal, for some the compensation mechanism studied here is active and for others it is not.

I think I may be repeating myself but it was a thought that came to mind while catching up with the latest posts

 

If both these studies are really seeing an association with duration, not severity, maybe there is some relation to the following study which found many cytokine differences between short duration and long duration ME/CFS, with most associations not affected by severity.

Distinct plasma immune signatures in ME/CFS are present early in the course of illness (2015, Science Advances)

 

So the Sato 6-feature classifier didn't replicate. The overrepresentation of IgM transcripts in the mild/moderate group (MECFSmm) was a fascinating incidental finding, although it didn't survive correction for multiple testing. The main result was the replication of VH3-30 increase in gene usage, although this was confined to MECFSmm (p=0.038, Cohen's D ~ 0.70 indicating a moderate effect size), but the lack of difference in the phenotypically similar VH3-30-3, and the lack of the same results in the MECFSsa group make it difficult to know what to make of this.

Strange that the MS group looks so similar to the healthy controls given the findings from other studies - e.g. the peripheral BCR repertoire results from this study.

 

No, but it's one of the few charts where it looks like both mild/moderate and severe are trending toward an increase and differ from the other two groups. Although here again, mild/moderate having more of an effect than severe is odd.

 

Does it matter that there are huge overlaps in the groups?

 

If you're hoping to be able to test someone's IgM and say whether they're ME/CFS or not it matters. But differences with overlaps are still useful. They show that on average the value is shifting for some reason, and it's not just randomness (although can't rule out randomness in IgM above since it's not significant.)

 

@Jonathan Edwards Does this make any sense: Could it be that B cells which encounter a certain specific antigen activate but for some reason never proliferate, class switch, or mutate? Maybe one way to explain increased IgM and VH3-30 without any markers of adaptive response. EBV does weird things to B cells, so maybe something similar?

 

Would be interesting to see the results of the ME/CFS groups combined (mild-moderate and severe) versus controls. I couldn't easily find that in the paper or supplementary material.

I couldn't find the dataset there, anyone been able to find it?

 

Never used the site before, but I got this message:
No records were found for PRJEB83659.

When you use the search option from the tool bar at the top, there’s a form for contacting them about issues. They might be able to solve it for you?
https://www.ebi.ac.uk/ebisearch/search?db=allebi&query=PRJEB83659&requestFrom=searchBox

 

From one of the authors on Bluesky:

 

My speculative 2c.

In addition to what forestglip has said, which is a good reply, my view is that most of the stuff that has been found "different" in the field has a good amount of population overlap and that I expect there is an array of things going wrong that lead to disease in synergy. ie: some of these disturbances are present or abnormal to varying degrees and in varying combinations depending on the individual and their specific clinical picture. Another unknown element is the causal biological chain of events.

Similar to what I am saying are the issues that arise with polypharmacy. Some of the side effects of drugs, or things going wrong from particular medical conditions, may be tolerable or even unnoticable on their own but in combination (with each other and with other factors such as genetics and environment) can tip over the edge towards the serious breakdown of biological processes. Suddenly a drug with ordinarily tolerable side effects can't be prescribed because it will cause hemorrhaging.

One might think of it as "the critical mass which overwhelms homeostasis". A critical mass that can be reached by many roads.

Another way to look at it would be that everything we see "different" is a straw upon the camel's back. But each camel has both a different weight bearing capacity and a different set of straws laid upon it, and some straws elicit the arrival of others.

The big picture questions are:
-Which straws when laid first lead to which other straws appearing? ie: which are the initiating straws and combinations of straws that lead to what we describe as ME/CFS?
-Why and how does each camel's apparent weight bearing capacity vary? - we know from studies of HLA alleles in COVID-19 infection that some individuals are predisposed towards asymptomatic infection purely on the basis of their genetics.

So to answer your question: if every camel with a broken back does not carry a particular straw, it does not mean that the straw would weigh nothing.

COVID-19 infection seems to be a particularly heavy straw. But it is not required to break the camel's back and does not always do so.

 

I would not expect changes in immunoglobulins of this sort to be causing ME/CFS symptoms. They are more likely to be epiphenomena reflecting some as yet hidden process. That being the case the overlap is not a worry. Alkaline phosphatase levels in RA patients are a bit higher on average than normals but with major overlap. The rise in levels probably represents Kuppfer cell activation, which was a useful clue to a unifying theory of disease mechanism but it is not the cause of joint pains.

 

The data is up. I have no idea how to parse it though. It looks like raw nucleotide sequence files. I wanted to see if there was a correlation between proportion of IGHV3-30 and levels of IgM in any of the groups.

 

I don't understand all this but at my very severe onset I had one abnormal IgM. A week or so later it was normal.

 

Just wanted to say I was probably wrong to make this statement since I realized they measured BCR Ig, not serum Ig. From what little I know, I can imagine there are ways the former could shift but not the latter.

 

I thought there was a good chance the IgM proportion would correlate to IGHV3-30, at least in the ME/CFS groups, suggesting that it is connected. I asked the author Audrey Ryback if she could plot those two metrics to check that, and she very kindly made those plots for me. It looks like I was wrong and there is no correlation, though.

All groups together


Groups plotted separately

 

Thread for Audrey Ryback's thesis which includes the same data as this paper, plus a couple other non-ME/CFS B cell repertoire related investigations:

Sequencing B cell receptor repertoires in human disease: applications in ME/CFS and in experimental malaria infection, 2024, Ryback