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

[Jonathan Edwards]

I did a quick Google on immune signal genes on X for what its worth. I gave these, in this order:

• TLR7 and TLR8: These genes encode receptors that recognize viral single-stranded RNA, a key part of the innate immune response.
  
  
• IRAK1: This is a crucial molecule in the TLR signaling pathway.
  
  
• NEMO: Also known as IKK$\gamma$, this gene is essential for the NF-κB signaling pathway, which is involved in inflammatory responses.

• CD40LG:
  Encodes the CD40 ligand, a key co-stimulatory molecule that regulates B cell activation and differentiation, and T cell survival.
  
  
• FOXP3:
  A transcription factor critical for the development and function of regulatory T cells (Tregs).
  
  
• BTK:
  Bruton's tyrosine kinase is vital for B cell development and function.
  
  
• IL-2RG:
  Encodes the common gamma chain, a component of multiple cytokine receptors essential for the development and function of lymphocytes.
  

• CXCR3: A chemokine receptor involved in the trafficking of leukocytes to inflammatory sites.
  
  
• TASL: Involved in signaling pathways downstream of certain cytokine receptors.
  

 

[forestglip]

• TASL: Involved in signaling pathways downstream of certain cytokine receptors.

I saw that TASL is also involved in lupus. Just some quotes I grabbed very quickly from abstracts:

TASL has a key role in SLE, Nature Reviews Rheumatology, 2025

Genome-wide association studies have identified numerous genes that are linked to the development of systemic lupus erythematosus (SLE), including TASL, IRF5, TLR7, TLR9 and SLC15A4.

Both Toll-like receptor 7 (TLR7) and TLR9 have known pathogenic roles in SLE pathogenesis; TASL–SLC15A4 interactions mediate the activation of IRF5 downstream of TLR7 and TLR9 signalling.

Despite the identification of this signalling cascade, the functional role that it has in SLE pathogenesis is unclear.

The role of TASL in the pathogenesis of SLE: X marks the spot, Annals of the Rheumatic Diseases, 2020

Interestingly, in its regulation of gene expression, TASL affects the IRF pathway but does not affect NF-κB or MAPK signalling.1 This pattern points to a unique role of TASL in the activation of innate immunity by the endosomal TLRs (figure 1).

 

[jnmaciuch]

CXCR3: A chemokine receptor involved in the trafficking of leukocytes to inflammatory sites

I’d be very interested if CXCR3 came up in DecodeME. Expression on neurons was crucial for mediating sickness behavior per the 2016 mouse study posted recently

https://s4me.info/threads/brain-end...or-and-cognitive-impairment-2016-blank.46844/

I saw that TASL is also involved in lupus. Just some quotes I grabbed very quickly from abstracts:

TASL has a key role in SLE, Nature Reviews Rheumatology, 2025


The role of TASL in the pathogenesis of SLE: X marks the spot, Annals of the Rheumatic Diseases, 2020

That might nicely explain an interferon response without other cytokines

 

[Jonathan Edwards]

Bruton's kinase (BTK) in double dose would be a good candidate for a general female predominance in autoatnibody-mediated disease I guess. I have been checking RA and so far there is no indication of TLR7 variants turning up, although I think they were only identified relatively recently as a potent risk factor in human lupus.

 

[chillier]

I did a quick Google on immune signal genes on X for what its worth. I gave these, in this order:

• TLR7 and TLR8: These genes encode receptors that recognize viral single-stranded RNA, a key part of the innate immune response.
  
  
• IRAK1: This is a crucial molecule in the TLR signaling pathway.
  
  
• NEMO: Also known as IKK$\gamma$, this gene is essential for the NF-κB signaling pathway, which is involved in inflammatory responses.
• CD40LG:
  Encodes the CD40 ligand, a key co-stimulatory molecule that regulates B cell activation and differentiation, and T cell survival.
  
  
• FOXP3:
  A transcription factor critical for the development and function of regulatory T cells (Tregs).
  
  
• BTK:
  Bruton's tyrosine kinase is vital for B cell development and function.
  
  
• IL-2RG:
  Encodes the common gamma chain, a component of multiple cytokine receptors essential for the development and function of lymphocytes.
• CXCR3: A chemokine receptor involved in the trafficking of leukocytes to inflammatory sites.
  
  
• TASL: Involved in signaling pathways downstream of certain cytokine receptors.

TASL stands for TLR Adaptor Interacting With Endolysosomal SLC15A4.

SLC15A4 is one of the 14 genes found in precisionLife's MECFS ukbiobank study.

TLR7/8/9 , SLC15A4 and TASL are in a TLR/interferon signalling axis:

proposed mechanism from this paper:

 

[Jonathan Edwards]

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? Finding such clones would be a very good way to counter the suggestion that disease perpetuation is just due to negative thinking (Dr Garner)! Epigenetic changes might of course do the same thing more reversibly?

 

[Liie]

Could there be any clues to question in title in one of the studies of cerebrospinal fluid?

For example:

Cerebrospinal fluid immune phenotyping

Central and peripheral kynurenine pathway metabolites in COVID-19

CSF immune cell alterations in women with neuropsychiatric Long COVID

Edit: I had the impression that the bone marrow had something to do with the spine. But apparently it hasn't; it is in many bones. So probably this post is not relevant. I have learned something about bone marrow.

 

[forestglip]

SLC15A4 is one of the 14 genes found in precisionLife's MECFS ukbiobank study.

TLR7/8/9 , SLC15A4 and TASL are in a TLR/interferon signalling axis:

Also in Precision Life's long COVID study:

Genetic Risk Factors for ME/CFS Identified using Combinatorial Analysis, 2022, Das et al

Our analysis identified seven genes that have been associated with diseases that have autoimmune components in both the literature and in other disease studies that we have undertaken, including COVID-19, rheumatoid arthritis and Sjögren’s syndrome (unpublished results).

Solute carrier family member 15 (SLC15A4) is found in the lysosomal membrane and has enriched expression in immune cells.

Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis, 2023, Taylor et al

In both Severe and Fatigue Dominant long COVID populations, we identified SNPs mapping to the genes ATP9A, INSR, CLOCK, SLC15A4 and GPC5.

But it doesn't look like anything in the area of this gene is significant in DecodeME. Maybe it requires PL's combinatorial approach.

Here is a plot of a lupus study (Wang 2021) and DecodeME overlaid. There's a very clear signal for lupus (blue) right at SLC15A4:



Zoomed out to see the nearest locus for ME/CFS:

 

[Fancymyblood]

Would HCQ be effective enough through it’s indirect endosomal TLR7/9 blocking effects? Far weaker and less selective than the new TLR7 antagonists, but it’s effective in lupus although I don’t know how much of that is mediated through TLR7.

I tried 400mg HCQ for a couple of months with no effects whatsoever.

 

[wigglethemouse]

I see that TLR7 is also associated with Sjogrens.......

TLR7 Signaling Drives the Development of Sjögren's Syndrome - PubMed

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS...

pubmed.ncbi.nlm.nih.gov

 

[wigglethemouse]

Bruton's tyrosine kinase

I see a BTK inhibitor has recently been FDA approved for chronic spontaneous urticaria. Chronic spontaneous urticaria is primarily caused by the activation of mast cells, which themselves are derived in bone marrow.

 

[wastwater]

Toll-like receptor 7 (TLR7) is a pattern recognition receptor that detects single-stranded RNA (ssRNA), often from viruses, and triggers downstream signaling pathways that induce innate immune responses — particularly type I interferon and proinflammatory cytokine production.

Here’s a breakdown of the key transcription factors activated by TLR7 signaling:

Major Transcription Factors Downstream of TLR7

Pathway​	Transcription Factor​	Main Function​
MyD88-dependent pathway	NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)	Induces proinflammatory cytokines such as TNF-α, IL-6, IL-1β.
	AP-1 (Activator Protein-1; includes c-Fos, c-Jun)	Regulates genes for cytokines and chemokines; often acts with NF-κB.
	IRF7 (Interferon Regulatory Factor 7)	Master regulator of type I interferon (IFN-α, IFN-β) production; especially important in plasmacytoid dendritic cells.
	IRF5	Induces proinflammatory cytokine genes and some IFN genes; contributes to macrophage polarization.

TLR7 → Signaling Cascade Summary

1. TLR7 detects ssRNA (usually in endosomes).
2. Adaptor recruitment: TLR7 recruits MyD88.
3. Downstream signaling: MyD88 forms a complex with IRAK4, IRAK1, and TRAF6.
4. Activation of kinases: This activates TAK1, which in turn activates
   • IKK complex → NF-κB
   • MAPKs → AP-1
   • IRAK1/IKKα → phosphorylation of IRF7 (and IRF5)
5. Transcriptional activation: NF-κB, AP-1, and IRFs translocate to the nucleus → drive expression of cytokine and interferon genes.

Key Points by Cell Type

• Plasmacytoid dendritic cells (pDCs): TLR7 strongly activates IRF7, leading to robust type I interferon production.
• Monocytes/macrophages: TLR7 mainly drives NF-κB, IRF5, and AP-1, producing inflammatory cytokines.
• B cells: TLR7 activation promotes NF-κB–mediated proliferation and antibody responses.

Summary

Main transcription factors activated by TLR7:

• NF-κB
• AP-1 (c-Fos/c-Jun)
• IRF7
• IRF5

Would you like me to include a diagram of the TLR7 signaling pathway showing where each transcription factor acts?

 

[wastwater]

Excellent question — you’re now asking about transcription factors that regulate the expression of TLR7 itself (i.e., what turns the TLR7 gene on or off), rather than those activated downstream of TLR7 signaling.

Here’s a detailed overview:

Transcriptional Regulation of
TLR7
(Upstream Regulators)

TLR7 expression is cell type–specific, cytokine-responsive, and modulated by immune activation. Several transcription factors and signaling pathways can upregulate or repress the TLR7 gene.


Positive Regulators (Upregulate TLR7 Expression)

Transcription Factor​	Mechanism / Context​	Key Notes​
IRF7 (Interferon Regulatory Factor 7)	Type I interferon (IFN-α/β) signaling induces IRF7, which can bind the TLR7 promoter.	Forms a positive feedback loop in plasmacytoid dendritic cells (pDCs).
IRF8	Promotes TLR7 transcription in dendritic cells and B cells.	Important for pDC and B cell TLR7 expression.
STAT1 / STAT2 / IRF9 complex (ISGF3)	Activated by IFN-α/β → binds ISRE (interferon-stimulated response elements) in the TLR7 promoter.	Major driver of IFN-induced TLR7 expression.
NF-κB	Can bind the TLR7 promoter and enhance transcription under inflammatory conditions.	Observed in macrophages and epithelial cells.
PU.1 (Spi1)	Binds to the TLR7 promoter/enhancer in myeloid and dendritic cells.	Required for basal expression of several TLRs.
C/EBPβ (CCAAT/enhancer-binding protein beta)	In macrophages, regulates TLR7 and other TLR family members.	Involved in differentiation and inflammatory gene regulation.
Estrogen receptor α (ERα)	In B cells, estrogen enhances TLR7 expression via ERα-mediated promoter binding.	Explains female-biased autoimmune responses (e.g., lupus).

Negative Regulators (Repress TLR7 Expression)

Transcription Factor​	Mechanism / Context​	Notes​
Blimp-1 (PRDM1)	Represses TLR7 transcription in B cells and pDCs.	Helps prevent excessive type I IFN production.
IRF4	Can antagonize IRF8 and repress TLR7 in certain B cell subsets.	Balances immune activation.
Glucocorticoid receptor (GR)	Activation by glucocorticoids suppresses TLR7 transcription.	Anti-inflammatory effect.
AhR (Aryl hydrocarbon receptor)	Can downregulate TLR7 and other TLRs upon activation by environmental ligands.	Links environmental sensing to immune tone.

Inducers of TLR7 Expression (via the above TFs)

Stimulus​	Pathway​	Effect​
Type I IFNs (IFN-α, IFN-β)	JAK–STAT → IRF7, ISGF3	Strong upregulation of TLR7 in pDCs, B cells, macrophages.
Estrogen	ERα binding	Upregulates TLR7 → contributes to female-biased immunity.
TLR stimulation (TLR3, TLR9)	NF-κB / IRF pathways	Indirectly increases TLR7 transcription.
Viral infection	IFN-mediated	Sustained TLR7 expression to enhance antiviral readiness.

Summary

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

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

Main repressors:

• Blimp-1 (PRDM1)
• IRF4
• Glucocorticoid receptor
• AhR

Would you like me to show the promoter architecture of the TLR7 gene (e.g., ISRE, NF-κB, and estrogen response elements) in a simple labeled diagram?

 

[Jonathan Edwards]

The apparent absence of a typical TNF (via NFkB) tissue response does perhaps point towards any TLR7/8 involvement being in B cells, which do not incite inflammation, although TNF is useful to induce CD55, CD21 and VCAM-1 on supporting cells like nurse cells and follicular dendritic cells.

I am not impressed by the idea of a classic autoantibody pathway. However, there is no doubt that antibody poopulations with some autoreactivity do get stirred up as by-products of a number of conditions like infections. They mostly seem irrelevant but maybe there is a weak spot in the program for switching off unwanted antibody after infection. Jo Cambridge has data on antibodies to signalling proteins that I think she has been too unwell to publish as yet. They may be secondary but all of these diseases tend to be exceptions that probe the rule of others in one way or another.

 

[Kitty]

I am not impressed by the idea of a classic autoantibody pathway.

Is that because the consequences eventually tend to make themselves apparent? Or can autoantibodies just exist without causing any detectable tissue pathology or organ malfunction?

 

[V.R.T.]

Jo Cambridge has data on antibodies to signalling proteins that I think she has been too unwell to publish as yet.

I'm sorry to hear Jo continues to be so unwell.

Her unpublished data sounds interesting, but I'm curious - how does a pathology involving antibodies to signalling proteins differ from a classic autoantibody pathway?

 

[Utsikt]

@wastwater could you please indicate if your posts are from AI or if you’re written them yourself?

 

[Jonathan Edwards]

Is that because the consequences eventually tend to make themselves apparent?

It is a combination of arguments - really what went into the Qeios piece with Jo and Jackie Cliff.

 

[Jonathan Edwards]

er unpublished data sounds interesting, but I'm curious - how does a pathology involving antibodies to signalling proteins differ from a classic autoantibody pathway?

Classical autoantibody-mediated disease nearly always has a stochastic time of onset and is limited to one or a very small group of tightly linked antigens. Lupus is the exception but there are plausible reasons why. The autoantibody levels tend to be 10-100 times higher than normal. Following infections autoantibodies are see across a broad spectrum of antigens at only slightly higher levels than normal and mostly do not cause any pathology that we know of. Where this happens for rheumatoid factor it is a different population of rheumatoid factors from that seen in RA.

The distinction may be specious and there may be an exception that probes the rule - which might be ME/CFS. But if one is trying to make sense of chronic diseases at a basic level I think these distinctions are useful.

 

[forestglip]

The apparent absence of a typical TNF (via NFkB) tissue response does perhaps point towards any TLR7/8 involvement being in B cells

Maybe specifically EBV-infected B cells? Just to pull from lupus research again, these authors think EBV may be necessary for lupus:

The toll like receptor 7 pathway and the sex bias of systemic lupus erythematosus, 2025, Frontiers in Immunology

Epidemiological evidence supports the idea that this near ubiquitous infection [EBV] is necessary but not sufficient for the expression of SLE as well as multiple sclerosis, and there some evidence in Sjögren’s disease (60–65). Recent studies have found that single nucleotide polymorphisms demonstrating genetic association with SLE or Sjögren’s disease are more likely to be found in promoter regions bound by the EBV transcription factor EBV nuclear antigen 2 (EBNA2) (66, 67).

Spoiler: References 60-67

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