Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

Jonathan Edwards said:
I may be wrong about this but I am not sure that NK cells have 'memory' in the usual sense. The rather similar CD57+ CD8 killer T cells would do. But I may be out of date.
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Thanks Jonathan this is all really useful. Over recent months I’ve been reading some papers about memory or memory like NK cells, which after exposure to cytokines can hang around for a long time with lower thresholds for activation.

I’m not sure if this ties in with the behaviour you mention, or is something different, but in reminds me of the fc gamma receptor behaviour in your paper, just in a different cell.

My conceptual understanding is fuzzy and my brain is not feeling particularly sharp atm so I’m struggling with the actual mechanisms and may be misinterpreting things. Maybe when I can get it together I’ll start a thread and see what others can make of it.
 
hotblack said:
Thanks Jonathan this is all really useful. Over recent months I’ve been reading some papers about memory or memory like NK cells, which after exposure to cytokines can hang around for a long time with lower thresholds for activation.
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That is something have not caught up with. It would not be surprising. These would not carry memory in the sense of remembering a specific antigen but could be remembering recent danger signals and remaining in a 'primed' state through an epigenetic modification.

And yes, this is very much the area jnmaciuch and I were discussing in terms of which cells were carrying 'immune memory' in ME/CFS - whether expanded T cell clones or macrophages with epigenetic modifications or indeed maybe NK populations. The BTN story seemed to feed in to that question.

What we have no data on so far is where such cells might be hiding. Cells in bloodstream may be a very unreliable guide or even a decoy. Maybe the old data on reduced NK function/numbers reflects a real shift in NK behaviour, but maybe the primed cells are hiding away and not circulating.
 
Jonathan Edwards said:
What we have no data on so far is where such cells might be hiding. Cells in bloodstream may be a very unreliable guide or even a decoy. Maybe the old data on reduced NK function/numbers reflects a real shift in NK behaviour, but maybe the primed cells are hiding away and not circulating.
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Thanks again, good to hear all this.

I need to read all the discussion here properly but have been wondering about the reported changes in NK function or talk of ‘exhausted’ NK cells and if this was more a case of them just being different. And on possibly relevowith Fluge and Mella’s work.

Where would they hide? It sounds like hiding in lymphoid tissue is a possibility again, but a lot of the ideas talked about seem hypothetical precisely because it’s difficult to study behaviour or cells in those locations.

There was mention of epigenetic changes, so certain points of the DNA with genes (like those responsible for IFN gamma production) being more exposed, so more readily available for transcription. I wondered if the methylation info from SequenceME could she some light here? Or would we hit the tissue dependency issues again?
AIUI there can be antigen specific behaviour (although maybe this was only in mice?) as well as this wider priming talked about.
One of the papers posted here https://www.s4me.info/threads/power...ller-cell-perspective-2025-sinha-et-al.50337/ I’ll post others in that thread later
 
Happened across a paper suggesting that stimulation of BTN2A1 on the surface of macrophages strongly affects their behavior. I have only had a chance to skim it so might come back later with criticisms of the paper. On first glance the basic findings seem to hold up (ignore the oversimplistic terminology of M1/M2 macrophages).

This suggests that there are probably multiple binding partners for BTN2A1 besides the gdT cell receptor. At least one has been identified which is expressed on DCs:


The main reason the first paper caught my attention is because it proved that extracellular engagement of BTN2A1 induces intracellular signaling cascades, which indicates that the intracellular region of the protein likely has binding sites for other signaling intermediaries. Since most of the identified BTN2A1 mutations in the AZ study were in the cytosolic portion of the protein, it paints those findings in a new light (i.e. the mutations might not have anything to do with the antigen “pocket”, which is only functional on BTN3A1 anyways, but rather intracellular signaling domains)

TLDR I think some molecular biology studies looking at the functional effect of those BTN2A1 mutations would be really insightful. The first paper uses a mAb that artificially stimulates BTN2A1 which would be very useful.
 
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jnmaciuch said:
TLDR I think some molecular biology studies looking at the functional effect of those BTN2A1 mutations would be really insightful. The first paper uses a mAb that artificially stimulates BTN2A1 which would be very useful.
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Did anyone ever contact these Cambridge BTN researchers? I know we talked about it but I can't remember what came of it.

@Jonathan Edwards

Kitty said:
Google sayeth this:
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Thinking of research proposals for the newest committee and BTN.

Would a cell imaging assay where you isolate gdT cells then using a live cell imager with exposure to zoledronate to induce IPP then measure the cytokine response be useful?

That would tell us if there’s an unusual/high response due to BTN variant?
 
It seems that prolactin can increase expression of BTN:

Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome:
We next investigated if prolactin-induced citrullination regulates the expression of lactation genes β-casein (Csn2) and butyrophilin (Btn1a1). Prolactin treatment for 12 h increased β-casein and butyrophilin mRNA expression; however, this increase was significantly inhibited by the pan-PAD inhibitor, BB-Cl-amidine (BB-ClA).
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This could also be a symptom of I am looking for connections between these things.
 
ChronicallyOverIt said:
It seems that prolactin can increase expression of BTN:

Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome:


This could also be a symptom of I am looking for connections between these things.
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Maybe a bit far fatched, but Dopamin D2 agonists (Cabergolin, but technically also Abilify) are used to inhibit prolaktin production.
 
Jonathan Edwards said:
It could, but it might just be rather important. With all the theories we have tossed about the thing I find hard to find a plausible story for is brain ramping up immune responsiveness. Maybe prolactin is involved.
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So the brain (particularly the pituitary gland) would "over-regulate" its immune reactivity via prolactin after a shock to the CNS (infection, medication, concussion, etc.). Could this represent an upstream mechanism that orchestrates both astrocytic activation (as seen by MELOPIS) and deregulates the entire system in the long term? Even then aunomic nervous system (POTS...) ?
Post-ejaculation syndrome? Sorry, but I've had this crap ever since my MECFS got worse...
How can we verify the role of prolactin in this through experiments?
 
I saw @DMissa commenting on an old thread about ROS. So I started googling BTN3A3 and ROS:

https://biokb.lcsb.uni.lu/publicati...s have demonstrated that,(OCR) and ROS levels.

“Previous reports have demonstrated that RPS3A positively regulates mitochondrial function and reactive oxygen species (ROS) levels. Our study has shown that overexpression of both BTN3A3 and RPS3A can increase cellular oxygen consumption rate (OCR) and ROS levels”
 
ChronicallyOverIt said:
I saw @DMissa commenting on an old thread about ROS. So I started googling BTN3A3 and ROS:

https://biokb.lcsb.uni.lu/publications/21828116-c6db-11ee-b346-0050569a791b#:~:text=Previous reports have demonstrated that,(OCR) and ROS levels.

“Previous reports have demonstrated that RPS3A positively regulates mitochondrial function and reactive oxygen species (ROS) levels. Our study has shown that overexpression of both BTN3A3 and RPS3A can increase cellular oxygen consumption rate (OCR) and ROS levels”
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I have been reading about this as well, today.

I think the mitochondrial angle as it is commonly conceived may be a trap though. IF there is a problem relating to free radicals I would guess that it is instead in a downstream enzymatic means of regulating their levels as opposed to how they arise upstream (based on what mitochondrial data we have)
 
jnmaciuch said:
Likely the latter. This would be an exceptionally difficult thing to get even indirect evidence for. The genetics hits might be enough to justify a therapeutics trial though. If it is something driven by gdT cells then cyclophosphamide would wipe them out too, and it has pretty good penetrance into brain and even bone marrow iirc. So we might have supporting evidence if that trial has a positive result. Something like an anti-gdTCR mAb would be way preferable to cyclophosphamide so I should think funding would be easier to get if it's pitched to funding bodies as "let us figure out if this other drug that is way less likely to give people cancer works just as well"


Not for this specific hypothesis, probably. OX40L is a co-stimulatory ligand that helps alpha-beta T cell activation specifically via professional antigen presenting cells (in the lymphoid organs). There isn't much evidence for it being relevant for gdT cell activation
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Properly not the drug you were thinking of, but could a DHODH inhibitor trial be useful for testing any of this?

There seems to be a properly designed trial (controlled, SF-36 endpoint) going on.

Randomized adaptive assessment of post COVID syndrome treatments (RAPID): a study protocol for a multicenter, randomized, controlled adaptive platform trial of treatment options for Post Covid Syndrome (PCS) on patients physical function including th

The majority of patients recovers from severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) coronavirus disease 2019 (COVID-19) without obvious sequelae, but a significant proportion suffers long-term consequences which have been termed ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

Apologies, if this is an unhelpful interjection.
 
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