Is the key pathology of ME/CFS in bone marrow?

[jnmaciuch]

I wonder if it is possible for haemopoietic stem cells to acquire mutations in non-coding DNA near Xist or some of these signalling genes that override the normal X inactivation of one X and this gets passed on to daughter cells. The result would be a bit like paroxysmal nocturnal haemoglobinuria where stem cell clones lose expression of CD55 (a complement inactivator) so that red cells are produced that lyse more easily. The clones appear spontaneously in midlife.

Is it even conceivable that in ME/CFS there are rogue clones like this simply overdosing the interferons pathways in such a way that they can be generated locally without due cause?

I like the thinking here, though the concern with a hard coded mutation is that it's harder to explain some of the temporal dynamics. Not impossible, but makes less sense to me than an epigenetic alteration. The explanation for remission would have to be a drop in clone numbers and vice versa for worsening of disease. My sense is that if this mechanism wasn’t something that lead to fatal complications like hemoglobinuria, we’d see much more sporadic worsening and improvement throughout the illness simply due to stochastic fluctuations in clone frequencies.

Epigenetic regulation would fit better to explain both pwME with unchanging disease severity for years, and those with changes due to exertion, infection, or some other processes that happen to involve relevant regulatory pathways.

Epigenetic changes might of course do the same thing more reversibly?

The reason I've been more inclined towards an epigenetic explanation involving interferon is because it would explain both baseline symptoms (from increased transcription of certain ISGs even without canonical interferon stimulation) plus it would prime the pathway to overreact to normal transient stimuli that induce an interferon response, potentially explaining PEM. A disease where baseline symptoms are solely mediated by ISGs themselves would bypass any need to explain the lack of other cytokines from canonical signaling pathways.

A reversible epigenetic change could be maintained long term provided that the signaling pathway gets stimulated often enough, keeping those chromatin regions open. If that stimulation can be achieved by a biological process that happens all the time, like neuron firing or muscle twitching, then you have a solid feedback loop. That's my thought behind calcium flux-mediated mtDNA release and type I interferon signaling via cGAS-STING or TLR9.

 

[jnmaciuch]

Plus mtDNA release through VDAC could absolutely also mean mtRNA release, implicating TLR7 and 8. [edit: Transiently, which would address prior objections about a lack of other cytokine signatures when measured at baseline]

 

[Jonathan Edwards]

And of course I forgot to mention that these clones with drifted genetic/epigenetic programmes may have some growth advantage and become more established with time (as in mitochondrial myopathies) but could conceivably be less good at surviving certain environments and sometimes regress. The latter always seems to happen less often in disease but then again we may miss it.

The other analogy here is MGUS (monoclonal gammopathy of unknown significance) which is a B cell clone that is too busy but not malignant, although it can precede myeloma. The only suggestion I have seen for an increased incidence of malignancy in ME/CFS is B cell lymphoma and I find it hard to link that in.

 

[Hutan]

Main transcription factors upstream of TLR7 (that regulate its gene expression):

• IRF7
• IRF8
• STAT1/STAT2/IRF9 (ISGF3)
• NF-κB
• PU.1
• C/EBPβ
• ERα

Epigenetic regulation would fit better to explain both pwME with unchanging disease severity for years, and those with changes due to exertion, infection, or some other processes that happen to involve relevant regulatory pathways.

There was that (unfortunately very small) Peppercorn 2025 paper that looked at differentially methylated fragments of genes in ME, LC and healthy controls.

STAT5A was found to be hypermethylated in both the LC and MC cohorts compared to the healthy controls. The hypermethylation means the gene is down regulated, there's less expression of it. STAT5A seems to have some female specific roles (it's involved in mammary gland development and milk production). But it also seems to engage (often with other STATs) in immune functions.

Throwing this into the mix:
Differential Contributions of STAT5A and STAT5B to Stress Protection and Tyrosine Kinase Inhibitor Resistance of Chronic Myeloid Leukemia Stem/Progenitor Cells

That 2013 study reported that STAT5 has a crucial role in hematopoietic stem cell maintenance, specifically the protection of the cells from various stresses.

Collectively, our results indicated that STAT5A exhibits the restricted property to limit .. normal stem/progenitor cell stress, independently of its canonical transcriptional activity. In line with these data, STAT5 downregulates ROS production in pre-B leukemic cell lines, in absence of detectable STAT5 tyrosine phosphorylation... Moreover, SRC/ABL kinases differentially affect nuclear translocation of STAT5A and STAT5B; accumulation of ROS correlates with reduced STAT5A—but not STAT5B—activity in aged macrophages; STAT5A shows differential tetramerization potential and selective posttranslational modifications

So, reduced expression of the STAT5A gene could be resulting in poorly functioning immune cells.

STAT5A has plenty to do with interferon.
STAT5 Contributes to Interferon Resistance of Melanoma Cells

The overexpressed STAT5 diminished IFNα-triggered STAT1 activation, most evidently through upregulation of the inhibitor of cytokine-signaling CIS.

So, increased expression of STAT5 was reported as reducing Interferon A triggered STAT1 activation.

However, if STAT5 expression is reduced in ME/CFS, as suggested by the Peppercorn finding, then there might not be that brake on Interferon A triggered STAT1 activation.

 

[Jonathan Edwards]

So, increased expression of STAT5 was reported as reducing Interferon A triggered STAT1 activation.

However, if STAT5 expression is reduced in ME/CFS, as suggested by the Peppercorn finding, then there might not be that brake on Interferon A triggered STAT1 activation.

It looks like the sort of thing you could build a story about every which way. However, if there were a block to one pathway downstream of interferons and not another, that might make some sense, especially if there was also a shift in negative feedback signals such as TGF beta.