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

From "Wiskott–Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans":

https://www.sciencedirect.com/science/article/pii/S0896841113001388

 

Might be just as important to look at where this gene is under-represented. I think in this paper studying chronic lymphocytic leukemia, IGHV3-30 in patients is similar to normal B cells, but IGHV3-30-3 is very under-represented.

Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene, 2005, Ghia et al

Here's the previous CLL paper this paper says it contrasts with. Not totally sure I understand, but I think it's saying that in healthy people, about 8.3% of B cells use the gene VH3-30.3. In CLL, people have cancerous B cells that make many copies of a single type of B cell. So each patient has an associated specific B cell. About 7.1% of patients had a malignant B cell population that included this gene. So just barely less than you would expect.
Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia, 1999, Hamblin et al

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This other gene IGHV3-30.3 was also higher in one of the earlier ME/CFS papers, Sato et al:

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I was having a hard time figuring out how exactly these two genes are related. Based on the naming scheme, I didn't know if IGHV3-30-3 was like a small section of the IGHV3-30 gene. But I think they are two separate genes that are just very similar. This is from the "Frequent use of IGHV3-30-3 in SARS-CoV-2 neutralizing antibody responses" paper:

 

According to Genecards WASF3 is a member of the WAS family of proteins. WASF3 was highlighted by the NIH study. Could this be relevant if there is something upstream in common regulating these?
https://www.ncbi.nlm.nih.gov/gene/10810

 

Why would IVGHV3-30 not be elevated in severe ME/ CFS? Hypothetically speaking!

 

Is the presence of relatively more B cells always caused by a relative increase to the need for those cells (i.e. that something is telling the body to make more of them), or can it be caused by the presences of more building blocks of that B cell, even if those building blocks were ordered for another reason?

Can it also be caused by an increase in their life span, or would that even out due to supply and demand?

Or are we looking for the initiatior for the formation of that type of B cells, if such a thing even exists? Are there multiple initiators for different stages?

would the initiator be unique to only that B cell, or could it be used in other things and the increase in B cells is just an unrelated byproduct of something completely different?

I think it’s pretty clear that I don’t know anything about how any of this works. Feel free to tell me if I’m going completely off track here.

 

Severe ME/CFS may be a different immune state than mild/moderate. It may still be the same disease, ie. people could switch between the two.

Alternatively assume the ME/CFS clinical concept contains two main biological processes. It’s not unlikely one of those includes more mild/moderate cases and the other more severe cases.

 

A very good question but it could suggest that severe ME/CFS tends to be due to a different starter pathway, even if the downstream events are the same. I think that there is also a significant possibility that samples from 'severe' cases in the cohort used (maybe from Sheffield?) are sourced in a rather different way from mild/moderate. That might introduce some artefacts. But it is certainly a puzzle.

A faint possibility would be that severe patients had not had viral exposures for a long time but that seems rather implausible to me.

 

Important points.

A key point is that each B cell arises from a precursor pro-B cell that has no commitment to making a particular antibody or using particular IgHV genes. Then it goes through an entirely random process of shuffling its Ig genes around in the chromosome and settling for a spliced together set of genes for heavy and light chains, including one HV option - maybe HV3-30 or HV4-34 or dozens of other options.

The next stage is that the B cell with its brand new antibody blueprint goes through checking systems to make sure the antibody is not a dud or dangerous. The gene combination might produce an V chain that curled up on itself and couldn't be stuck to an L chain. The antibody might be anti-self. If it looks bad the B cell may be allowed to re-try a new gene set (receptor editing) but otherwise it is told to die.

The simple outcome of this ought to be that the billion B cells made each day always have the same random mix of antibody types (there are vast numbers of possible amino acid sequences so no two days' antibodies are quite the same). But if there is a defect in complement there may be failure of a complement mediated checkpoint that allows autoantibodies through (this is lupus). Apart from that we are still roughly expecting a similar random proportion of HV usages.

The point being that individual antibody molecules are never made to order. The system is never instructed to make specific antibodies. It only ever positively selects useful antibodies from the random mix.

The the B cell goes out into blood and on into spleen or lymph node where it competes with other B cells for being selected. The powerful selection signal is the B cell being given some foreign antigen to sample. But selection depends on a lot of factors. It seems that B cells carrying an antibody with certain HV gene usage my be better at competing in follicles for instance. HV4-34 B cells cannot compete at all and have to hang around outside with the T cells.

And yes, life span and trafficking routes will skew the proportions you pick up in different tissues and blood.

So the story is very complex but there are certain things that seem to crop up that may point to something specific. Moreover, Audrey found no evidence of selection being dependent on one specific antigen, which pushes things towards these contextual preferential survival factors.

 

Over significant fields of time? Does infection duration factor in? Is the IgG vs IgM consideration a thing with infections that persist? Is this not a gene thing as much as it is a function of chronicity?

As an example: syphilis.

 

Maybe so if it's the Sheffield cohort. The group didn't have the funding or staff resources to visit severely affected people at home, so samples could only be taken from those able to travel to Pond St. Wouldn't rule out everyone with severe ME/CFS, but the group might be skewed to less severe.

As a subset of people with ME/CFS have experienced everything from significant remission to severe illness, maybe it's possible there can be shifts in some of these pathways or processes? Though it would have to account for the fact that changes in severity level can occur quite rapidly, and also gradually over periods of years.

 

Actually, maybe this aspect is easier to explain.

Infections aren't always accompanied by obvious symptoms. If a viral infection's enough to trigger a shift, you'd probably expect to see them. In some versions of the story it might be more surprising if shifts didn't happen.

 

The mention of Whiskott-Aldrich makes me want to ask if this is potentially closely related to the WASF3 finding?

WASF3 is the Wiskott-Aldrich Syndrome Protein Family Member 3.

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

 

Could a higher selection be dependent on genetic mutations like above?

It seems to be beneficial for certain types of cancer according to my googling. Plausible?

This is what happened in the study at the beginning of this comment.

 

Yeah, I think you’re right. I might have jumped to conclusions, I believe I googled LDH Leukemia and found that elevated LDH was a poor sign, and therefore thought that normal LDH was good. My bad!

 

Sorry if I’ve missed this, still getting my head around the thread, but
why would the ratios of these be different? One type being overproduced or the others underproduced? Or over or under-consumed?

 

Having read the rest of the thread I think the answer to my question is somewhere between ‘yes’ ‘lots of potential reasons’ and ‘it’s complicated’…

 

This is a fascinating finding and I hope it is the first step on a road to getting all of us some answers, but I do find the fact it wasn't replicated in severe ME worrying in a personal level. I'm sure i'm not the only person who is concerned that when
the severe state is triggered something irreversible happens. Whether it is reversible or not, becoming severe felt like slipping into another disease state. Like something shifted or mutated into something worse. Everything seemed to change and so many new symptoms sprang up. That is all very subjective and unscientific I'm sure. People who recover from severe to mild or moderate over time would seem to disprove this, but they do seem to be the exception not the rule.

 

Different starter pathways is interesting. But how could severe ME have a different starter pathway if some people start off mild and stay that way for many years before becoming severe, and some lucky people who have been severe for many years recover to a moderate or mild level over time?

And is there a way that if this finding is not present in severe people, they could still have the same upstream cause but somehow its not increasing the hv3-30 levels in the severe form of the disease? Like the disease process is expressed differently downstream in mild/mod and severe?

I don't buy the idea that severe ME is a separate condition. Perhaps some people are more vulnerable to becoming severe somehow but the idea that it is caused by a wholly different disease process seems unlikely to me.