Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

[jnmaciuch]

There is definitely “clonal expansion” downstream of gdTCR activation using all the same pathways as in the alpha betas, it seems. Just a much smaller repertoire set compared to alpha-betas. So there could be some repertoire skewing.

Correction to this point after attending a recent lecture: gdT cells have much fewer options for V, D, and J regions compared to abT cells, but they actually can generate a high degree of diversity because they have a unique feature of incorporating multiple D regions.

However, even with this correction I am not sure how relevant this for BTN interactions, since the extracellular portion of BTN3A1 is what binds (and may well not bind to the CDR3 region on the gdTCR anyways). There might be some conformational changes induced by the phosphoantigen binding but the protein structure paper seems to suggest that’s probably not the case. So I don’t really see a case for T cell receptor specificity here

[edit: irrelevant here but I just thought it was cool—apparently gdTCRs are longer and can actually wrap around antigens to a certain degree. Meaning that their binding to an antigen resembles B cell/antibody binding more than a standard TCR-MHC-peptide situation. Could be relevant in other disease contexts]

 

[mariovitali]

So many people on statins I think we’d know now if it helped. I do think the loss of function is far more intriguing than the lipid angle, still I’d like to look at all possibilities until we confirm more!

I was thinking the contrary since statins inhibit the production of mevalonate pathway products.

 

[Felis Catus]

Statins have been prescribed for LC, including COVID-triggered ME/CFS, as a part of triple therapy for microclots, Patterson's protocol (in combination with maraviroc) and some clinicians prescribe it with blood thinners (different than the triple therapy). That increases the pool of ME/CFS patients who've tried them.

 

[ChronicallyOverIt]

I was thinking the contrary since statins inhibit the production of mevalonate pathway products.

I was thinking it would decrease the IPP thus lowering the proposed threshold for the gamma tcells to trigger, but yes it would also decrease Cq10 etc… mixed bag.

 

[Jonathan Edwards]

So I don’t really see a case for T cell receptor specificity here

That seems to be the logical conclusion.

One thought in that context: can BTN3A1/2A1 dimers bound to intracellular phosphoantigen compete with other ligands for te relevant gdTCR that do actually engage CDR with antigen? That would raise a possible route for underfunctioning BTN2A1 allowing TCR engagement to generate signals thourgh other routes. (Or is the relevant gamma delta chain combination 'blind' to extracellular antigen?)

 

[Jonathan Edwards]

It seems that Vgamma9delta2 can bind to several other extracellular ligands, including lipids, as well as BTN3A1/2A1 dimers so there does seem to be a possibility of increasing other binding by reduced competition but as far as I can see so far Vg9d2 doesn't bind MHC restricted foreign peptides in the standard way. But if this is all an aberration of self interactions maybe in the context of expanded 'innate T populations' then specific foreign peptides were never necessary to the story. We still need a plausible 'epigenetic' shift to confer long term dysregulation and break the rules that applied before the trigger for the susceptible individual.

Maybe this is all about handling lipids in the context of a 'danger' response with the infection just providing a non-specific danger trigger.

I keep looking over to left field to see if anything has turned up but if it has I have missed it so far.

 

[V.R.T.]

Is there anyway the BTN story could coalesce with this long covid cd8+ T Cell/IFNy paper?

Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid, 2024, Krishna et al

Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid Abstract After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid...

s4me.info

Obviously we're talking about a different type of t cells with gdT but I'm just wondering if these are two different possible stories or if there could be fragments of a larger story.

 

[Felis Catus]

I was thinking it would decrease the IPP thus lowering the proposed threshold for the gamma tcells to trigger, but yes it would also decrease Cq10 etc… mixed bag.

Some clinicians advise starting CoQ10 before/when starting a statin. Don't know how prevalent is that and how efficient is the supplementation, though. Just saying in case it means anything.

 

[Nightsong]

Butyrophilin-2A1 directly binds germline-encoded regions of the Vγ9Vδ2 TCR and is essential for phosphoantigen sensing

Phosphoantigen sensing combines TCR-dependent recognition of the BTN3A IgV domain and germline interaction with BTN2A1

Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

 

[Jonathan Edwards]

Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

Many thanks. i just have to figure out which MR1 this is!

 

[Jonathan Edwards]

OK that's Class I-Related protein 1 (MR1) that presents riboflavine things.

This is getting very complicated but might actually land somewhere interesting. This links to MAIT cells (Jackie Cliff).

 

[Jonathan Edwards]

Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

It's fascinating if bewildering. Of particular interest they had a patient with a major T subset expansion with relevant interaction profile and a strange illness. Probably not ME/CFS but if these things can develop other glitches maybe they can develop an ME/CFS glitch.

 

[jnmaciuch]

One potentially left field connection with BTN3A1 and my type I interferon interest:

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Apparently BTN3A1 has an additional intracellular function where the phosphoantigen binding region also binds TBK1, involved in IFN signal transduction downstream of cytosolic DNA/RNA detection. Seems to act as some sort of chaperone

Not sure if BTN2A1 can be linked easily, there might be a story of negative regulation via competitive binding since BTN2A1 binds to BTN3A1 at the same region (meaning nonfunctional BTN2A1 might enhance IFN signaling). The paper tested multiple BTN knockdowns and only 3A1 had a significant effect on IFN-b production. Though they only tested one dsDNA antigen that seems to signal via a specific pathway. One other DecodeME candidate gene from another locus, ZNFX1, is a cytosolic RNA sensor that signals through a different pathway.

 

[Jonathan Edwards]

All good stuff.

One thing I was reminded of is that we should not be surprised if these proteins have several indirectly related or even unrelated functions. Almost all of them have two stereochemically separate functions - doing a job A through ligand site A and binding through ligand site B to whatever controls their expression, in the context of execution of job A. And lots of molecules engage various ligands that are all involved in some general response - as for corticosteroids. And other molecules appear to have taken on several roles having been 'borrowed' from earlier functions in evolution. VCAM-i is an endothelial adhesion molecule, a B cell 'nurse' requirement in bone marrow, a follicular dendritic cell ligand for B cell emperipolesis in lymph node, and a macrophage traffic regulator in synovial intima.

 

[SNT Gatchaman]

Re: statins and muscle dysfunction.

I only know three people (all women) who've taken them, and they all complained of muscle pain.

One found changing to a different type solved the problem, the others stopped them. When my cousin told her GP how achy and heavy her muscles felt, he said she'd only developed pain because she'd read about it on Facebook.

None of them have ME/CFS, but it makes sense that if you're one of the people who gets side effects, they might make existing pain worse.

The GP who thinks everything is a social media contagion should probably get up to date. From Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation (2025) —

Statin side effects are presented in ~10% of treated individuals and commonly include skeletal muscle complaints varying from mild cases of myalgia along with muscle weakness, stiffness, tenderness, and cramps to rare but life-threatening cases of rhabdomyolysis culminating in autoimmune-mediated necrotizing myositis. These statin-associated muscle symptoms (SAMS) typically affect the proximal musculature in the lower limbs.

Blockade of the mevalonate pathway by statins may directly affect several branching metabolic pathways in addition to cholesterol synthesis, resulting in coenzyme Q 10 deficiency and loss of protein prenylation, both of which may contribute to SAMS. However, statin lactone prodrugs, inactive as HMG-CoA reductase inhibitors, have been associated with adverse drug reactions, suggesting the existence of off-target mechanisms that account for SAMS Moreover, SAMS have been linked to statin-induced intracellular Ca 2+ release, impacting Ca 2+ signaling pathways in skeletal muscle. Nevertheless, the molecular mechanism(s) that underlies SAMS remains poorly understood.

Our results from mice imply that not only dominant pathogenic RyR1 mutations like YS but also recessive mutations like TM can predispose heterozygous individuals to SAMS, suggesting a future direction for translational research.

Taken together, the structural, functional, and physiological data provided here suggest a crucial role of dysfunctional RyR1 in contributing to adverse simvastatin side effects in skeletal muscle, making RyR1 a potential therapeutic target to mitigate SAMS.

 

[NelliePledge]

My experience with the GP was really good she listened to my explanation of how I had realised I had been needing max dose of paracetamol for weeks since starting on statin whereas before I wouldn’t need that on better days. I expected her to suggest changing to another type but as I’ve lost weight she said it wasn’t necessary to keep taking them as my cardiac risk score was reduced.