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

[jnmaciuch]

There is a persistent suggestion that thyroid autoantibodies are more common in people with ME/CFS, which maybe should be taken seriously. But again, there are all sorts of ways one might explain that which don;t necessarily imply the ME/CFS itself requires autoantibodies.

I’ve been mulling over the idea that the presence of thyroid antibodies during the resolution period after acute infection may be a relevant predisposing factor to ME/CFS. Temporary infection-induced thyroiditis is a documented phenomenon—it may even occur at a much higher prevalence than we know, simply because it could resolve on its own within a few days or weeks and someone may never have gotten around to a doctor who would screen for those antibodies.

Given thyroid hormone’s relevance to gene regulation, intracellular calcium (CD38, neuron and/or muscle function), and a couple other threads that have come up as potentially relevant, I was thinking it could be a good culprit for a global signal that aids resolution of certain immune processes following infection. Obviously I’d jump to interferon here.

If the stochastic appearance of anti-thyroid antibodies interferes with thyroid function during and after acute infection, it might leave someone more vulnerable to a feedback loop involving mechanisms that were active during infection and failed to adequately resolve. The antibodies themselves may not remain pathologically high after infection, but the damage was already done, and some pwME may retain slightly higher than normal levels long term.

Not to mention the sex disparity in Hashimoto’s is similar to ME/CFS (though the exact ratio is a somewhat under debate).

 

[Braganca]

She was an impatient for 3 months receiving very strong chemo (inc rituximab). Remarkably, it worked. I feel there may be a genetic link between NHL and ME as I know of a few other families who have had both in the family

Non Hodgkin’s lymphoma has been mentioned in the past as having some sort of increased occurrence with ME but never knew if the evidence was there. Just remember it being brought up online from my first few years.

 

[Kitty]

Just remember it being brought up online from my first few years.

Yes, it's been around along time, but I never saw an article with references supplied. I remember it being quite prominent in the MEA literature at one time.

 

[forestglip]

What we do not know is exactly which genes on X are important - whether TLR7, TLR8 or whatever, but the answer is not going to be in looking for gene variants. The effect is not due to gene variants but chromosome variants, otherwise known as sex.

What a WGS might show is a link to a variant of TLR7. There is a rare variant of TLR7 that links strongly to lupus. That would tell us that TLR7 is relevant but it still does not tell us directly that it is the normal TLR7 on women's XXs that is the major risk for them.

I'm not sure if I'm not fully understanding, but I don't see the reason to be so pessimistic about finding variants.

So say we have evidence that a second X chromosome greatly increases risk. Ok, where do we go from there? How do you figure out which gene on X?

There's a good chance, although maybe not a certainty, that there exist variants that increase or decrease expression of the gene of interest. If you amass a large enough sample, controlled for sex, you should expect those variants to be significant, hopefully pointing right to the gene.

So it seems to me that if we end up seeing any variants in the upcoming DecodeME ChrX analysis, especially if the variant is known to increase expression of a gene, it might be pointing to exactly what causes females to have higher risk.

 

[bobbler]

Yes I think I know the exact type of pain you mean. It does often seem to come from inside the bone, if that is possible.

me too. particularly the lower leg, now feet somewhat

 

[Jonathan Edwards]

I'm not sure if I'm not fully understanding, but I don't see the reason to be so pessimistic about finding variants.

I am not particularly pessimistic but it wouldn't necessarily tell us the common reason for women being more at risk.

So say we have evidence that a second X chromosome greatly increases risk. Ok, where do we go from there? How do you figure out which gene on X?

Most likely you check the literature to see if someone has already made an inspired guess - like for lupus.

So it seems to me that if we end up seeing any variants in the upcoming DecodeME ChrX analysis, especially if the variant is known to increase expression of a gene, it might be pointing to exactly what causes females to have higher risk.

But I suspect it is relatively unlikely to work out that simple. Moreover, finding a risk link to rare variants is by definition not the main reason for the sex bias. What does @ME/CFS Science Blog think!

 

[SNT Gatchaman]

Maybe TLR7 expression feeds in to pathways, that may involve interferons, which TLR7 is good at inducing, that shift the cell production microenvironments in marrow to produce more of certain sorts of myeloid or lymphoid subsets. Something a bit like seasonal changes in the fish market.

TLR7 could explain the 3:1 female predominance in most autoimmune disease, I guess, through an effect on interferons that simply made B cell survival in germinal centres a bit easier, making an autoimmune clonal error easier. But lupus is 9:1 so maybe TLR7 can have another effect through another environment, which might be bone marrow. If this operates in lupus and ME/CFS, but not in most other autoimmune disease, that might explain why lupus and ME/CFS both have incidence peaks earlier on - if the effect was not directly related to accumulation of random Ig gene rearrangements and mutations over a lifespan.

A few potentially relevant references —

TLR7 gain-of-function genetic variation causes human lupus (2022)

Spoiler: Abstract

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1,2,3,4,5,6,7, evidence of lupus-causing TLR7 gene variants is lacking.

Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10,11,–12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2,3-cGMP10,11,12, and was sufficient to cause lupus when introduced into mice.

We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells.

We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Web | PDF | Nature | Open Access

The toll like receptor 7 pathway and the sex bias of systemic lupus erythematosus (2025)

Spoiler: Abstract

Systemic lupus erythematosus (SLE) predominately affects women with a ratio of females-to-males of about 9:1. The complement of sex chromosomes may play and important role in the mechanism of the sex bias. Previous work has shown that men with Klinefleter’s syndrome (47,XXY) as well as women with 47,XXX are found in excess among SLE patients well as among Sjogren’s disease, systemic sclerosis and idiopathic inflammatory myositis.

In cells with more than one X chromosome, all but one is inactivated. However, X chromosome inactivation, as mediated by the long noncoding RNA X-inactive specific transcript, or XIST, is not complete with approximately 10% of genes in the non-recombining region of the X chromosome escaping X inactivation.

In the TLR7 signaling pathway, both the TLR7 and TLR adaptor interacting with endolysosomal SLC15A4 (TASL) escape X inactivation. Comparing male and female immune cells, there is increased TLR7 signaling related to increased expression of these genes in cells with more than one X chromosome.

Cells with more than one X chromosome also express XIST, while cells with one X chromosome do not. XIST, as a source of ligand for TLR7, has also been shown to increase TLR7 signaling. Thus, we propose that both these mechanisms operating in immune cells with more than one X chromosome may act in a mutual way to mediate an X chromosome dose effect for the sex bias of autoimmune disease.

Web | PDF | Frontiers in Immunology | Open Access

Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus (2025)

Spoiler: Abstract

While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target.

Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138-and CD138+ PC, including putative LLPC (CD19-CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression.

Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro, but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor.

In summary, these findings show evidence of IFN activation in BM PC from SLE.

Web | PDF | Frontiers in Immunology | Open Access

B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells (2018)

Spoiler: Abstract

Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways.

Through bone marrow chimeras, DNA-reactive B cell transfer, and GC-specific Cre mice, we confirm that IFNαR signaling in B cells promotes autoreactive B cell development into both pathways. Transcriptomic analysis reveals gene expression alterations in multiple signaling pathways in non-GC and GC B cells in the absence of IFNαR. Finally, we find that T1IFN signaling promotes autoreactive B cell development in the AFC and GC pathways by regulating BCR signaling.

These data suggest value for anti-IFNαR therapy in individuals with elevated T1IFN activity before clinical disease onset.

HIGHLIGHTS
• Type 1 IFN (T1IFN) signaling in B cells promotes autoreactive B cell development

• T1IFN signaling drives autoreactive B cell development by regulating BCR signaling

• T1IFN signaling in GC B cells causes loss of tolerance and ANA production

• T1IFN signaling is not required for immunization-induced B cell responses

Web | PDF | Cell Reports | Open Access

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And in mice (not humans) you can have a duplicated TLR7 gene on the Y chromosome

Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication (2006)

Spoiler: Abstract

Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased toward nucleolar antigens because of increased expression of TLR7, a single-stranded RNA-binding innate immune receptor.

The TLR7 gene is duplicated in Yaa mice because of a 4-Megabase expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y chromosomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.

Web | PDF | Science | Paywall

 

[Utsikt]

If the stochastic appearance of anti-thyroid antibodies interferes with thyroid function during and after acute infection, it might leave someone more vulnerable to a feedback loop involving mechanisms that were active during infection and failed to adequately resolve. The antibodies themselves may not remain pathologically high after infection, but the damage was already done, and some pwME may retain slightly higher than normal levels long term.

Would this involve permanent damage to the thyroid? Or are you referring to something else with «damage»?

 

[Kitty]

Would this involve permanent damage to the thyroid? Or are you referring to something else with «damage»?

I read it as meaning the feedback loop that results in ME/CFS had already been triggered during an episode of short-lived thyroiditis, not that there's lasting damage to the thyroid.

 

[ME/CFS Science Blog]

Or to put it another way, a GWAS on twenty patients would show TLR7 was in a risk factor DNA segment (X) - assuming that you controlled against a group of normal controls not selected with a 3:1 sex ratio.People with ME/CFS are much more likely to have two X chromosomes than the general population unselected. So all the SNPs on the X chromosome in DecodeME would give a p value of 10-^100 or something if compared with an unselected population.

Was wondering if TLR7 is important, wouldn't we expect to see differences in SNPs that influence the expression of TLR7?

Haven't read the entire thread, so might have missed something.

 

[forestglip]

But I suspect it is relatively unlikely to work out that simple. Moreover, finding a risk link to rare variants is by definition not the main reason for the sex bias.

The hypothesis is that the dose of a gene matters for ME/CFS. One way of increasing dose is being female. But you'd expect any other mechanism that increases expression/function of the gene, if such a mechanism exists, to also increase risk. Such as a genetic variant. Maybe even an environmental factor.

A common variant might not increase dose quite as much as being female, but if this gene is one of the main risk factors for ME/CFS, then I think there's a good chance it comes up significant.

 

[Jonathan Edwards]

Was wondering if TLR7 is important, wouldn't we expect to see differences in SNPs that influence the expression of TLR7?

I guess so, but are there any such SNPs in the library used?

 

[Kitty]

Been burrowing down a few rabbit holes ... seems TLR7 inhibition is being discussed as a potential therapy for lupus, and promising-looking small molecules have been developed. So if it did eventually turn out to be important in ME/CFS, there's work to build on when looking for a treatment.

 

[Jonathan Edwards]

A common variant might not increase dose quite as much as being female, but if this gene is one of the main risk factors for ME/CFS, then I think there's a good chance it comes up significant.

Sure, I am just trying to make sure people do not confuse related but separate processes. The risk of that does seem to be real. Some members are finding it hard to get their heads around it!!

 

[forestglip]

I guess so, but are there any such SNPs in the library used?

Yes: https://www.gtexportal.org/home/gene/TLR7

The variants listed under "Significant Single-Tissue eQTLs for TLR7" are associated with changes in expression of TLR7.

They're categorized by tissue. There is a chance there are no variants that increase expression in the tissue that matters.

And it's also possible there are more variants of interest that aren't listed because the effect size was too small to be significant [edit: or the tissue/cell-type wasn't tested]. So just being near a gene like TLR7 might be the only clue we have in that case.

 

[Jonathan Edwards]

seems TLR7 inhibition is being discussed as a potential therapy for lupus,

Useful find.

Yes: https://www.gtexportal.org/home/gene/TLR7

Ah, I thought the question referred to SNPs on other chromosomes included in the DecodeME SNP library. Yes, some SNPs near TLR7 on X would be expected to come up with something as well as variants of TLR7 protein itself.

 

[Adrian]

I am not particularly pessimistic but it wouldn't necessarily tell us the common reason for women being more at risk.

Could there be a relationship with hormones - in terms say of triggering mechanisms. I'm saying that as I have a vague memory that the norway study showed the rates for children are more even until adolescence.

 

[AliceLily]

I've only had one very painful experience with bone marrow and that was at my very severe onset ME which was triggered by the only flu I can remember ever having. For two days I had severe aching/drawing out pain from one of my shin bones. It felt like it was coming out of the center of the bone.

 

[jnmaciuch]

Would this involve permanent damage to the thyroid? Or are you referring to something else with «damage»?

I read it as meaning the feedback loop that results in ME/CFS had already been triggered during an episode of short-lived thyroiditis, not that there's lasting damage to the thyroid.

Yes what @Kitty said

 

[Hutan]

I was tempted to suggest that you 'feel ME/CFS in your bones'

I've referred to the pain I get during PEM as 'bone-crushing', or feeling as though I have been run over by a steam roller. I've seen others do that too. Perhaps that has nothing to do with ME/CFS pathology. But, I've talked about swelling during PEM before - I wonder if that occurs in bone marrow in PEM?

Bone marrow is also well innervated, at least in sensory terms. It is highly sensitive to pressure change in particular.

What do you mean about 'highly sensitive to pressure change' Jonathan? What causes that pressure change?

Maybe there is something is going wrong with the nerves in the bone marrow? It does seem like an area where neurons and the immune system are interacting in important ways. We know that nerves in the bone marrow signal for immune cell development, so if there is something wrong with the nerves, there could be something wrong with the immune cells. And vice versa.

(a bit of speculation deleted)