Kitty
Senior Member (Voting Rights)
What did you think about the apparent loss of a specific type of neuron in postmortem ME/CFS brains? It's a very small sample, but the finding looked interesting all the same.
Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)
- Thread starter Hutan
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What did you think about the apparent loss of a specific type of neuron in postmortem ME/CFS brains? It's a very small sample, but the finding looked interesting all the same.
Jonathan Edwards
Senior Member (Voting Rights)
that's what I think.
It's disappointing to see Chris using that Vroegindeweij violin chart on hair cortisol. I've discussed those hair cortisol findings here (see also other posts upthread of that one). That Knoop team's study is small and unreliable, and the 12 people with ME/CFS had a mean hair cortisol level well in excess of the controls after a three month behavioural intervention (despite the increases in hair cortisol not being linked to recovery*). Those people were reportedly able to increase hair cortisol levels in response to the challenge of the intervention, but that did not make them well.
Three other studies did not find differences in hair cortisol.
We urgently need a study to see if that finding of CRH neuron loss is replicated. I understand that it seems like a beguilingly neat answer to the problem of ME/CFS, and perhaps it is the answer, but it is very hard to square with an unbiased assessment of the findings on cortisol in ME/CFS.
* ME/CFS group mean hair cortisol level went from 0.49 at baseline to 0.70 post-intervention. Control mean was 0.59. Edited to add: A major difference in participant mean age could account for the lower baseline value in the ME/CFS group.
Three other studies did not find differences in hair cortisol.
We urgently need a study to see if that finding of CRH neuron loss is replicated. I understand that it seems like a beguilingly neat answer to the problem of ME/CFS, and perhaps it is the answer, but it is very hard to square with an unbiased assessment of the findings on cortisol in ME/CFS.
* ME/CFS group mean hair cortisol level went from 0.49 at baseline to 0.70 post-intervention. Control mean was 0.59. Edited to add: A major difference in participant mean age could account for the lower baseline value in the ME/CFS group.
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ScoutB
Senior Member (Voting Rights)
Yeah @Hutan I thought of your cortisol thread when that video first came out.
Chris even mentions he'd like people to tell him he's wrong -- I think it just goes to show what a mess the ME/CFS literature landscape is. Claims get repeated over and over in abstracts as truth, giving everyone (esp. newcomers) the impression something is well established, when that's not the case at all. Researchers almost have to conduct their own critical lit review on every fact they want to know about.
I have fantasized of making some kind of mini 'review' on topics like these. It could just be collecting the studies of the cortisol thread into a table summarizing their findings (and whether or not clinically relevant), anything we can say about reliability (incl. sample size), and any other caveats ("morning cortisol could be affected by patients having later waking times"). Could just go in the first post of the thread? Then we could point researchers to that, not as definitive proof of anything, but so they could easily get a sense of the strength of the evidence for themselves...
Chris even mentions he'd like people to tell him he's wrong -- I think it just goes to show what a mess the ME/CFS literature landscape is. Claims get repeated over and over in abstracts as truth, giving everyone (esp. newcomers) the impression something is well established, when that's not the case at all. Researchers almost have to conduct their own critical lit review on every fact they want to know about.
I have fantasized of making some kind of mini 'review' on topics like these. It could just be collecting the studies of the cortisol thread into a table summarizing their findings (and whether or not clinically relevant), anything we can say about reliability (incl. sample size), and any other caveats ("morning cortisol could be affected by patients having later waking times"). Could just go in the first post of the thread? Then we could point researchers to that, not as definitive proof of anything, but so they could easily get a sense of the strength of the evidence for themselves...
Kitty
Senior Member (Voting Rights)
Yes, definitely.
But if the finding's real, it might be more complicated than just cortisol levels. Maybe other tissues secrete enough CRH to keep cortisol levels adequate, and the loss of those specific neurons results in a related but different issue.
Well I won't go as far as to say "wrong" but I would question the point on bacteria metabolites when we're mostly describing viral infection related onset. (Perhaps gut microbial translocation as a secondary effect? Maybe some other effect on gamma-delta Ts?)
But, I would like to re-up this earlier comment from @jnmaciuch, particularly given Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study (2026)
Just to go back to the GeneCards descriptions for BTN2A1 and BTN2A2 —
BTN2A1 said:
BTN2A2 said:
ChronicallyOverIt
Senior Member (Voting Rights)
This got me thinking, is there a way to link this to @DMissa newest paper? Would the lipid accumulation seen in that paper trigger the BTN2A1 or BTN3A1, thus triggering the T-cells?
Jonathan Edwards
Senior Member (Voting Rights)
I cannot track down much about the supposed role of BTN2A1 n lipid metaboism beyond the interesting fact that variants of the gene confer risk for lipid-linked diseases like coronary artery disease.
I suspect that the relevance to T cells is more about shifting thresholds for innate responses generally than about any specific role of bacterial products.
I need to have another think about this. I think a genetic variant could confer risk in two very different ways. It seems that ME/CFS involves an acquired reset of one or more regulatory mechanisms. I think immune and nervous systems are the only likely candidates. So BTN2A1 could be involved in tripping a 'bistable' regulatory pathway into a bad state. T cells would fit for that. But conceivably so might hypothalamic circuits involved in lipid regulation. The one thing that seems against that is no obvious link between ME/CFS and either high or low weight.
The gene variant might, alternatively, simply make a tissue more susceptible once regulation has shifted. That would apply to organ systems that carry the downstream symptom-generating burden. I think nervous system might be the most likely there and it might be something to do with membrane lipid. T cell gamma delta receptors might be a complete red herring.
I suspect that the relevance to T cells is more about shifting thresholds for innate responses generally than about any specific role of bacterial products.
I need to have another think about this. I think a genetic variant could confer risk in two very different ways. It seems that ME/CFS involves an acquired reset of one or more regulatory mechanisms. I think immune and nervous systems are the only likely candidates. So BTN2A1 could be involved in tripping a 'bistable' regulatory pathway into a bad state. T cells would fit for that. But conceivably so might hypothalamic circuits involved in lipid regulation. The one thing that seems against that is no obvious link between ME/CFS and either high or low weight.
The gene variant might, alternatively, simply make a tissue more susceptible once regulation has shifted. That would apply to organ systems that carry the downstream symptom-generating burden. I think nervous system might be the most likely there and it might be something to do with membrane lipid. T cell gamma delta receptors might be a complete red herring.
ChronicallyOverIt
Senior Member (Voting Rights)
I’m trying to piece together my idea of linkage. I think there is precedent of T-cells activating in presence of lipid accumulation, but I’m out my depth here:
Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells - PMC
T lymphocytes expressing the T cell receptor (TCR)-γδ recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR-γδ cells. In tumor cells, blockade of ...
pmc.ncbi.nlm.nih.gov
V.R.T.
Senior Member (Voting Rights)
Due to the mention of nucleus acumbens on another thread, I googled it and BTN2A1 together on a whim and got this. Not sure if it means anything.
www.proteinatlas.org
Brain tissue expression of BTN2A1 in nucleus accumbens - The Human Protein Atlas
Expression of BTN2A1 (BT2.1, BTF1, BTN2.1) in nucleus accumbens tissue.
www.proteinatlas.org
Kitty
Senior Member (Voting Rights)
If anyone wants to play with the options on the protein atlas, here it is:
www.proteinatlas.org
It doesn't seem to have much specificity to brain region or brain tissue type, and in blood it isn't substantially unregulated in disease.
BTN2A1 protein expression summary - The Human Protein Atlas
BTN2A1 (BT2.1, BTF1, BTN2.1) protein expression summary.
www.proteinatlas.org
It doesn't seem to have much specificity to brain region or brain tissue type, and in blood it isn't substantially unregulated in disease.
V.R.T.
Senior Member (Voting Rights)
I came across this post in the thread for Nath's checkpoint inhibitor trial
I was reading about how btn2a1-inhibitors can be analogous to PD-1 earlier last week, something possibly connected to that genetic hit?
https://synapse.patsnap.com/article/what-are-btn2a1-inhibitors-and-how-do-they-work?
mariovitali
Senior Member (Voting Rights)
Using the analytical framework I developed over the years and after having as inputs the genes overlapping with Fibromyalgia, here are the outputs :
1) DNA Methylation that @Chris Ponting mentioned comes up as highly relevant
2) Triglycerides come up for some reason as an important concept connecting these genes.
3) Ubiquitination
4) Mevalonate pathway. Note that mevalonate pathway has been identified previously via machine learning analyses :
https://www.s4me.info/threads/machine-learning-assisted-research-on-me-cfs.5015/page-7#post-185951
1) DNA Methylation that @Chris Ponting mentioned comes up as highly relevant
2) Triglycerides come up for some reason as an important concept connecting these genes.
3) Ubiquitination
4) Mevalonate pathway. Note that mevalonate pathway has been identified previously via machine learning analyses :
https://www.s4me.info/threads/machine-learning-assisted-research-on-me-cfs.5015/page-7#post-185951