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

[Jonathan Edwards]

Another thought is th`t it seems TLR7 genotypes can predispose to lupus and you can have lupus without any inflammation (and the genesis of autoantibodies can precede any clinical signs for some time). Even where there is inflammation in lupus it is often not associated with much evidence of TNF production in terms of CRP rise, so we know that TLR7 can be involved in pathology without going down the traditional NFkB pathway.

 

[jnmaciuch]

That seems a reasonable objection but what if TLR7 or 8 was ligated in specific cell populations in very specific places - maybe cells that do not generate things like TNF. It would certainly be an argument against macrophage activation. What about something like gamma delta T cells specifically in bone marrow?

You’d have the same problems with myeloid precursors in the bone marrow. Less TNF than a mature macrophage, but they still have strong NFkB signaling to other ends.

Plus the bone marrow niche is extremely sensitive—if there was constant stimulation in the marrow, you would expect to see altered developmental trajectories in circulating populations, especially myeloids. Bone marrow cancers and latent infections in the marrow both present with shifts in multiple hematopoietic cell types

 

[Jonathan Edwards]

You’d have the same problems with myeloid precursors in the bone marrow. Less TNF than a mature macrophage, but they still have strong NFkB signaling to other ends.

But the myeloid precursors might not have their TLR7 tickled.
My point is that this pathway might be very cell specific.

And as said above, in lupus we seem to have a disease generated in a way that is known to be influenced by TLR7 genotype without necessarily having any general signs of activation of any particular pathway other than aberrant B cell selection and immune complex formation. Cytopenias occur but they are very idiosyncratic. The classic picture of lupus is a raised ESR from abnormal Ig populations without a raised CRP.

 

[jnmaciuch]

But the myeloid precursors might not have their TLR7 tickled.
My point is that this pathway might be very cell specific.

Sure, though then you end up with a similar problem as any autoantibody theory where you have to do a lot of gymnastics to explain how the mechanism works only in a specific way that would align with illness presentation, with only weak reason to believe it’s relevant in the illness in the first place.

 

[Jonathan Edwards]

Sure, though then you end up with a similar problem as any autoantibody theory where you have to do a lot of gymnastics to explain how the mechanism works only in a specific way

Well, we have needed a good deal of gymnastics to work out what was going on in RA and lupus. Local tissue microenvironments are likely to be crucial for all these things.

 

[jnmaciuch]

Well, we have needed a good deal of gymnastics to work out what was going on in RA and lupus

You can use the same logic to argue for pretty much any theory, so positive evidence in favor of the mechanism being relevant is what matters.

From what I gather from this thread, the reasons for thinking TLR7 are a link to female preponderance and the potential for triggering an immune response. Which puts it on pretty much equal grounds with an autoantibody theory, and I’m not particularly seeing the point in chasing down either lead without a reason to think it’s more viable than anything else.

 

[Jonathan Edwards]

From what I gather from this thread, the reasons for thinking TLR7 are a link to female preponderance and the potential for triggering an immune response. Which puts it on pretty much equal grounds with an autoantibody theory, and I’m not particularly seeing the point in chasing down either lead without a reason to think it’s more viable than anything else.

The lupus evidence suggests that incomplete inactivation of a second X may be relevant and TLR7 (and 8) are the candidate genes we have encountered so far. TLR7 came up as a risk factor for lupus I think on a rare gene analysis. Whether we have data for other autantibody mediated diseases I don't know but the sex ratio for lupus is about the square of most other autoimmune diseases so an additional lupus-specific effect of XX through TLR seems plausible over and above maybe another reason for female predominance of antibody-mediated disease (or maybe the same).

We have been chasing autoantibodies for a decade or more in ME/CFS and nothing really fits. You cannot find them and the inective trigger is not typical for autoantibody mediated disease anyway. The relatively early peak of incidence in teens isn't typical of autoantibody mediated disease but it is very much in line with lupus. If we do not explore a possibility like this we are pretty much left with ME/CFS being more common in women because they are worriers and fantasisers, God forbid.

I think we need something very specific as a loophole in the response to infection software to explain ME/CFS. Each autoantibody mediated disease looks to involve some very specific loophole. TLR7 is used by a whole range of cells and it might mediate a specific pathway involving any one of them. So I don't see that we can predict how it would show up. Nobody would have predicted it would show up as thrombocytopenia, arthralgia and membranous nephropathy in lupus.


So I disagree!!

 

[Jonathan Edwards]

I will see what Audrey thinks in a couple of weeks time.
She doesn't miss much !

 

[jnmaciuch]

If we do not explore a possibility like this we are pretty much left with ME/CFS being more common in women because they are worriers and fantasisers, God forbid.

The remaining search space includes the entire rest of the X chromosome plus unknown effects of sex hormone ratios. The only people jumping immediately to misogyny if TLR7 doesn't make sense are bigots.

The lupus evidence suggests that incomplete inactivation of a second X may be relevant and TLR7 (and 8) are the candidate genes we have encountered so far. TLR7 came up as a risk factor for lupus I think on a rare gene analysis. Whether we have data for other autantibody mediated diseases I don't know but the sex ratio for lupus is about the square of most other autoimmune diseases so an additional lupus-specific effect of XX through TLR seems plausible over and above maybe another reason for female predominance of antibody-mediated disease (or maybe the same).

One very simple way to make sense of the squared sex ratio of lupus is that the trigger for TLR7 activation and the antigen of disease-driving antibodies are the very same nucleic acids. TLR activation is known to enhance antigen presentation capacity. [Edit: so elevated risk from TLR dosage * general elevated risk to develop autoantibodies]. Which means that female preponderance in other autoimmune diseases could very well not be explained at all by TLR7.

I think we need something very specific as a loophole in the response to infection software to explain ME/CFS.

I agree. Though you haven't given me any additional reasons as to why TLR7 specifically is relevant in ME/CFS, and the problem still remains of explaining how a receptor present on multiple cell types would only get activated by an antigen on one mystery cell type that doesn't trigger a cascade of other cytokines we would expect even in the bone marrow. If TLR7 comes up as relevant in DecodeME's analysis then that would be a reason to invest time in the mental gymnastics. Without that, or any other evidence or logic showing how TLR7 fits the picture well, we're just running well beyond the evidence of one speculative correlation in a mouse paper. They didn't do any knockouts or drug targeting to confirm that TLR7 has any causal role in the long term cognitive dysfunction.

 

[Jonathan Edwards]

One very simple way to make sense of the squared sex ratio of lupus is that the trigger for TLR7 activation and the antigen of disease-driving antibodies are the very same nucleic acids.

That sounds neat.

Which means that female preponderance in other autoimmune diseases could very well not be explained at all by TLR7.

Agreed but then we need another explanation which we haven't had a thread on yet.

problem still remains of explaining how a receptor present on multiple cell types would only get activated by an antigen on one mystery cell type that doesn't trigger a cascade of other cytokines we would expect even in the bone marrow.

Well it seems to happen in lupus.
I guess that B cells are the easiest ones to blame because they pick up stuff through surface Ig and might not channel rogue nucleic acid through other routes. But I agree that we have argued there isn't much going for them in ME/CFS (unless you consider the daratumumab preliminary data).

we're just running well beyond the evidence of one speculative correlation in a mouse paper.

I have found that a very useful way to find new ideas. And dismiss others.

 

[richie]

Would hemophagocytosis be of any relevance to this?

 

[Jonathan Edwards]

Would hemophagocytosis be of any relevance to this?

I associate that with rather extreme activation but that may be a mistake. Passing bits of garbage around in parcels seems to be relevant to various diseases. Dunno.

I realise that the motivation for this thread is probably a bit opaque but I didn't want to start off with a huge spiel about loads of things. Maybe tomorrow I will try to focus in again on the motivation - which has to do with innervation and signals to brain as well as another hiding place we have not explored much.