Genetics: BTN2A2 and BTN3A3

[Jonathan Edwards]

It would all fit together nicely. But then there always seems to be a way to fit things together nicely. I think Jackie Cliff is pleased the way data are coming out.

I am reminded of the film Amelie. If some set of T cells are causing trouble they are doing it in a very surreptitious way. Nobody can see where they are or what they are doing. Things turn up in research data but we cannot see how they got there or who they belong to. Maybe the writing on the wall is part of the story. Like the photos in the booths in Amelie.

Maybe one could image patterns of writing attached to TGF beta binding proteins on matrix and read what messages the T cells or macrophages have left there.

 

[V.R.T.]

Maybe one could image patterns of writing attached to TGF beta binding proteins on matrix and read what messages the T cells or macrophages have left there.

Are you talking about the kind of biopsies you describe here?

The first step would be to look at patterns of adsorbed signalling proteins on matrix fibres using biopsies and immunochemistry. Calibrating between individuals would probably be hard. I would look for changes in patterns. One the the best bits of evidence for our rheumatoid theory was that the immunoglobulin receptor CD16 is expressed on macrophages and adsorbed on to elastic fibres at exactly the site where rheumatoid nodules occur. I would not expect anything quite as clear-cut as that for ME/CFS but something equally striking might turn up around muscle or something.

Taking biopsies is not easy but if one knew exactly what was looking for a fairly small series might provide a very useful clue.

And if so do you expect any studies like this to happen in this new post-DecodeME landscape? You mentioned Wusts group as a possibility further down that thread.

 

[Jonathan Edwards]

Are you talking about the kind of biopsies you describe here?

No, in this instance I was talking about trying to find patterns by imaging techniques without taking tissue samples. It is a long shot but maybe technologies will come along.

 

[Jonathan Edwards]

I have tried to get it bit more information on BTN2A2 / its butyrophyllin protein.

It appears to be an MHC Class I protein. It is not a typical antigen presenting Class I protein as in HLA-A, -B and -C but it is a transmembrane protein of the same immunoglobulin supergene family. It also appears to be quite widely expressed on antigen presenting cells, as are both Class I and II. That includes expression on thymic epithelial cells, which interact specifically with T cells in triage by antigen recognition. It also includes breast epithelial cells and milk fat globule membrane, which expresses other MHC proteins like DR, presumably as part of some sort of immune signalling to fetus, along with maternal antibody transfer. (I remember in 1979 when my brother suggested I looked for HLA-DR [then called IA] in synovium because it was involved in immune response he [a breast tissue biologist] was chuffed because he had heard it was on milk fat globule membrane.)

So although this protein is pretty widely distributed, that is pretty standard for MHC molecules that function via interactions with T cells. Apparently some T cells express BTN2A2 but again, they do for other MHC.

The reviews talk of roles in moderating T cell functions like gamma interferon production. Some focus on regulatory T cells and some on gamma delta. My impression is that the interaction is fairly general. But I have not yet found suggestions that BTN2A2 does much else. I risk from a gene like this would certainly fit with the gist of the model Jo C, Jackie and I suggested - the FcRI aspect was only ever a way to try to make the model consistent with female predominance.

This analysis may be wrong but to me the gene looks like a very important clue. I was initially excited by the idea that DecodeME might have found an HLA link. That turned out to be a bit of a false start, although there still seems to be a suggestion of DQ. But in some ways BTN2A2 looks more relevant because it looks to be involved in a rather general 'innate' signalling mechanism to T cells (in the sense of not being tied to any particular peptide, which seems to me problematic).

 

[V.R.T.]

I have tried to get it bit more information on BTN2A2 / its butyrophyllin protein.

It appears to be an MHC Class I protein. It is not a typical antigen presenting Class I protein as in HLA-A, -B and -C but it is a transmembrane protein of the same immunoglobulin supergene family. It also appears to be quite widely expressed on antigen presenting cells, as are both Class I and II. That includes expression on thymic epithelial cells, which interact specifically with T cells in triage by antigen recognition. It also includes breast epithelial cells and milk fat globule membrane, which expresses other MHC proteins like DR, presumably as part of some sort of immune signalling to fetus, along with maternal antibody transfer. (I remember in 1979 when my brother suggested I looked for HLA-DR [then called IA] in synovium because it was involved in immune response he [a breast tissue biologist] was chuffed because he had heard it was on milk fat globule membrane.)

So although this protein is pretty widely distributed, that is pretty standard for MHC molecules that function via interactions with T cells. Apparently some T cells express BTN2A2 but again, they do for other MHC.

The reviews talk of roles in moderating T cell functions like gamma interferon production. Some focus on regulatory T cells and some on gamma delta. My impression is that the interaction is fairly general. But I have not yet found suggestions that BTN2A2 does much else. I risk from a gene like this would certainly fit with the gist of the model Jo C, Jackie and I suggested - the FcRI aspect was only ever a way to try to make the model consistent with female predominance.

This analysis may be wrong but to me the gene looks like a very important clue. I was initially excited by the idea that DecodeME might have found an HLA link. That turned out to be a bit of a false start, although there still seems to be a suggestion of DQ. But in some ways BTN2A2 looks more relevant because it looks to be involved in a rather general 'innate' signalling mechanism to T cells (in the sense of not being tied to any particular peptide, which seems to me problematic).

So you're saying this gene could potentially be more useful/relevant than the kind of HLA link that turned out to be a mirage? That's encouraging. I was a little concerned your pre DecodeME enthusiasm might have been heavily weighted by that HLA skyscraper.

BTN2A2 does seem like it could fit quite well (in terms of my surface level understanding anyway)

On that note- I've been looking into DQ a little and it seems really relevant to a lot of the stuff we've been talking about lately (T cells, graft vs host, autoantibody response).