Ron Davis’s big immune study is looking at HLA genes (HLA, WTF?) Here’s the story. [Simon M blog]

[Jaybee00]

@deleder2k thanks. I imagine the Fluge paper is about to come out?

Why am I nervous?

It’s associated with psoriasis.

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00954/full

Aside from HLA-C*06:02 psoriasis associated with HLA-C*12:03, HLA-C*07:01, HLA-C*07:02, HLA-C*07:04, HLA-B*27, and HLA-B*57. F

 

[deleder2k]

Where have you heard that from deleder2k?

A presentation by dr. Saugstad (Oslo University Hospital). No written documentation or specifics..

 

[Snow Leopard]

A presentation by dr. Saugstad (Oslo University Hospital). No written documentation or specifics..

Was that for ME or another illness?

You'd need either a whole exome sequence or at the very least HLA sequencing to know if you had the variant or not.

http://www.iedb.org/details_v3.php?type=mhc&id=4
https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/get_allele.cgi?HLA00436

http://hla.alleles.org/alleles/index.html

 

[FMMM1]

Was that for ME or another illness?

You'd need either a whole exome sequence or at the very least HLA sequencing to know if you had the variant or not.

http://www.iedb.org/details_v3.php?type=mhc&id=4
https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/get_allele.cgi?HLA00436

http://hla.alleles.org/alleles/index.html

While I know basically nothing about this I'm intrigued. Anyone got an update?
For one there's always been the association with autoimmunity but B-cell autoimmunity faded after the the failed rituximab trial. The other thing is purely supposition. I recall a researcher saying that she felt something new would have to be developed to understand this disease I.e. the tools were not there; so here's a new tool - HLA sequencing. In fact it looks like Ron Davis group are having to develop the techniques. Don't get me wrong, this technology is not outside our grasp but it does need to be refined.
I'm just not sure why it's taking so long - money? I.e. if you can do one HLA sequence then doing X thousand takes more resources I.e. rather than a new discovery.
Very interesting about the link to psyorisis; I have it and my family member with severe undiagnosed fatigue (ME?) has it. I recall some talk about the incidence of diseases, considered to be autoimmune, being higher in families with ME.

I assume all of the whole genome sequencing data for HLA should be treated with caution I.e. since Ron's team are having to revise the existing sequencing techniques for HLA genes.

Lots of assumptions here, some data, I.e. interim data from the project, would be nice.

@Jonathan Edwards I think you reckon T-cell autoimmunity is a way to destroy your career, or at least waste years; what do you make of this research area?

 

[wigglethemouse]

I assume all of the whole genome sequencing data for HLA should be treated with caution I.e. since Ron's team are having to revise the existing sequencing techniques for HLA genes.

Do you have a reference for that @FMMM1? From what I remember Montoya in his video talks mentioned he sequenced HLA and thought he had exciting findings and was close to publishing. When Ron Davis looked at them Montoya mentioned they would do a new study, and the paper was never published.

His latest NIH funded project will look at HLA.
https://projectreporter.nih.gov/project_info_description.cfm?aid=9724350&icde=31258613

Secondly, the human leukocyte antigen (HLA) locus – the most challenging region of the human genome to sequence, and the most relevant to individual differences in immunology – will be sequenced in a large cohort of ME/CFS patients to determine whether HLA variants may be contributing to the T cell activity observed, and/or to increased susceptibility to the disease.

I seem to remember Ron Davis saying they would leverage HLA experience at Stanford. According to this webpage Stanford Blood Center has an expert profiling lab on HLA that I would guess his team is working with.
https://stanfordbloodcenter.org/research-labs/hla-lab/

The Stanford Histocompatibility & Immunogenetics Laboratory (HLA Lab) performs state of the art and cutting edge histocompatibility and genetic testing for solid organ and bone marrow transplantation as well as for disease associations and drug resistance/susceptibility.

The HLA Lab offers a wide selection of testing services, has an active research and development program and houses and curates a bio-repository of patient specimens. It services Stanford Health Care, Lucile Packard Children’s Hospital Stanford, Kaiser, as well as other transplant centers.

It is accredited by the American Society for Histocompatibility and Immunogenetics (ASHI), CLIA, and the state of CA for high complexity testing. The HLA Lab performs over 60,000 tests per year and employs a staff of more than 50 full-time team members.

 

[FMMM1]

Do you have a reference for that @FMMM1? From what I remember Montoya in his video talks mentioned he sequenced HLA and thought he had exciting findings and was close to publishing. When Ron Davis looked at them Montoya mentioned they would do a new study, and the paper was never published.

His latest NIH funded project will look at HLA.
https://projectreporter.nih.gov/project_info_description.cfm?aid=9724350&icde=31258613


I seem to remember Ron Davis saying they would leverage HLA experience at Stanford. According to this webpage Stanford Blood Center has an expert profiling lab on HLA that I would guess his team is working with.
https://stanfordbloodcenter.org/research-labs/hla-lab/

I recall Ron talking about the difficulties sequencing HLA genes :; Stanford were working on special techniques for HLA genes. So if you have a standard genome sequence then I assume that the inference is that the data may not be reliable I.e. for HLA.
We could of course ask someone from OMF. - if anyone has a contact.
If I come across anything further then I'll post here.

 

[Jonathan Edwards]

@Jonathan Edwards I think you reckon T-cell autoimmunity is a way to destroy your career, or at least waste years; what do you make of this research area?

I am not quite sure what to make of new interest in HLA. The main HLA gene types were identified in the 1980s and by the 1990s most HLA-associations had been identified. People looked for HLA associations in ME back in the 1980s I think. It is now possible to look at finer subtypes using direct sequencing rather than other methods but I am not sure of the chances of finding anything. A 20,000 cohort GWAS is being planned but we already have data on several smaller cohorts with no consistent HLA association as far as I know.

HLA genes encode the antigen presenting proteins of MHC Class I and II. The C locus is class I and is more likely to be linked to T cell responses than B cell-based antibody responses. I don't really believe in T cell autoimmunity but I do believe in diseases being due to T cell overactivity - as in ankylosing spondylitis, psoriasis and Reiter's syndrome. A link with an HLA-C locus with overlap with psoriasis would make sense for an ME subset. It is conceivable that his would be an HLA-C type given specifically by all four digits (e.g.0704) rather than the first two digits, that correspond roughly to the subtypes known in the 1990s.

 

[wigglethemouse]

If I come across anything further then I'll post here.

There is some more info here and a 2012 paper "High-throughput, high-fidelity HLA genotyping with deep sequencing" by both Davis's
https://www.omf.ngo/2018/07/25/julie-wilhelmy/

Through a collaboration with Mark Davis, our group decided to focus on Human Leukocyte Antigen (HLA) profiling. As this region of the genome is highly variable and the products of these genes are a major factor in the human response to infection and in autoimmunity, it became evident that obtaining this information from patients with immune-related diseases would be very valuable so we developed a high throughput method to determine the sequence of these genes in many individuals (http://www.pnas.org/content/109/22/8676).

And more info here. It could be technology already developed in the 2012 paper but it's not clear.
https://www.omf.ngo/2018/06/26/davis-nih-grant/

In this study, Mark Davis will look at an array of T-cells to determine the breadth and extent of the T-cell activation in ME/CFS. He’ll pair that with new technology developed by Ron Davis which gives researchers a better handle on the genes used to capture those pathogenic antigens. They’re found in the most mysterious part of our genome in the HLA locus.

EDIT: Here is Ron's quote from a 2018 talk
https://www.omf.ngo/wp-content/uploads/2018/05/Transcript-Dr-Ron-Davis-update-May-2018.pdf

Also, to do that study we have to do the HLA region, and we have worked out a method for that sequencing, which has now been commercialized. It's used at Stanford and throughout the world for transplant matching, and it looks like it's been very very successful. I'm told that rejections are now at a lower frequency

Also, we will do the KIR sequence. It's very much like the HLA. The HLA is a major locus that determines self, and it's very involved in autoimmunity. The KIR locus seems to be more involved in interacting with viruses. From the Severely Ill patient study, the KIR locus is showing up to be a very important locus. It's hard to sequence. We're going to be working with the clinical HLA lab to carry out that sequencing.

So they will be using the Stanford Blood Center HLA lab that I posted above for both HLA and KIR sequencing.
https://stanfordbloodcenter.org/research-labs/hla-lab/

 

[wigglethemouse]

@FMMM1 This is the latest info on the study I've seen suggesting an ongoing T-cell response. It was from the recent ME conference in Sweden in Oct 2019 and presented by Jonas Berquist on behalf of the OMF team. How is your Swedish?

https://youtu.be/XZcxLocioYU?t=9567

 

[FMMM1]

@FMMM1 This is the latest info on the study I've seen suggesting an ongoing T-cell response. It was from the recent ME conference in Sweden in Oct 2019 and presented by Jonas Berquist on behalf of the OMF team. How is your Swedish?
View attachment 9045

https://youtu.be/XZcxLocioYU?t=9567

Thanks @wigglethemouse this is interesting I.e. an update. I don't have any Swedish; anyone here know if you can do text to speech and then Google translate?
I may ask if there's a transcript.

 

[deleder2k]

I hope someone can translate. I understand Swedish, but I can't do it at the moment. With respect to my post about cyclo and hla-c*07:04; it seems that PWME with ME after Canadian criteria with hla-c*07:04 have an increased chance of responding to cyclo treatment for their ME symptoms. Haukeland has teamed up with Oslo University Hospital. It is great to see bright researchers working together.

 

[mango]

I hope someone can translate.

Maybe possibly perhaps @Anna H can help..? (Maybe if you can make a transcript of that specific part, we could then run it through Google Translate and tidy it up together?)

 

[Jonathan Edwards]

@FMMM1 This is the latest info on the study I've seen suggesting an ongoing T-cell response. It was from the recent ME conference in Sweden in Oct 2019 and presented by Jonas Berquist on behalf of the OMF team. How is your Swedish?

That looks like the Mark Davis data from a while back. I though that the findings had not panned out.

 

[wigglethemouse]

That looks like the Mark Davis data from a while back. I though that the findings had not panned out.

You are right. That Sweden slide seems to be old data from Montoya samples according to Mark Davis's NIH talk. In this talk he said they were just getting started with the new Ron Davis cohort, had just received the HLA data needed for the work, and may also need to start looking at TCR's on CD4 cells in addition to CD8.



You probably understand more what he is talking about than I do. I'll need to watch a few more times. If you do watch I'd appreciate your thoughts on the talk.

 

[FMMM1]

That looks like the Mark Davis data from a while back. I though that the findings had not panned out.

Haven't watched the video yet. I gather there were two projects i.e. Mark Davis's project on clonal expansion in CD8+ T cells (?) and Ron Davis's HLA study. I think I recall that Mark Davis's project on clonal expansion did not work out i.e. clonal expansion was found in the controls. However, I haven't seen anything on Ron Davis's HLA study, I was hoping there'd be some indication of how it's going. Maybe they had to do a lot of method development, on HLA sequencing, and that's what is holding up publication of the data.

 

[Anna H]

Maybe possibly perhaps @Anna H can help..? (Maybe if you can make a transcript of that specific part, we could then run it through Google Translate and tidy it up together?)

Hi, yes I can help! I'll start making a transcript right away

 

[FMMM1]

Maybe possibly perhaps @Anna H can help..? (Maybe if you can make a transcript of that specific part, we could then run it through Google Translate and tidy it up together?)

I think the clonal expansion of T-cells is unlikely to be interesting (hopefully I'm wrong). However, if talk deals with HLA and KIR sequencing then I'm certainly interested.

Hi, yes I can help! I'll start making a transcript right away

Thank you very much. I'm particularly interested in whether Jonas mentions HLA or KIR sequencing. However, I'd pretty much be interested in any clues on how OMF research is going.

Jarred Younger's video presentation (in English at the same Conference) is interesting, their experiments (microglia activation) worked out - they're preparing to publish.

 

[FMMM1]

I am not quite sure what to make of new interest in HLA. The main HLA gene types were identified in the 1980s and by the 1990s most HLA-associations had been identified. People looked for HLA associations in ME back in the 1980s I think. It is now possible to look at finer subtypes using direct sequencing rather than other methods but I am not sure of the chances of finding anything. A 20,000 cohort GWAS is being planned but we already have data on several smaller cohorts with no consistent HLA association as far as I know.

HLA genes encode the antigen presenting proteins of MHC Class I and II. The C locus is class I and is more likely to be linked to T cell responses than B cell-based antibody responses. I don't really believe in T cell autoimmunity but I do believe in diseases being due to T cell overactivity - as in ankylosing spondylitis, psoriasis and Reiter's syndrome. A link with an HLA-C locus with overlap with psoriasis would make sense for an ME subset. It is conceivable that his would be an HLA-C type given specifically by all four digits (e.g.0704) rather than the first two digits, that correspond roughly to the subtypes known in the 1990s.

Thank you very much for this. Solve ME/CFS have funded Bruno Paiva i.e. to work on "class II molecules of the major histocompatibility (MHC)"[https://solvecfs.org/bruno-paiva/].

I'm not sure how Paiva's work fits; HLA's, MHC's, --- it is all quite technical.

 

[Jonathan Edwards]

Thank you very much for this. Solve ME/CFS have funded Bruno Paiva i.e. to work on "class II molecules of the major histocompatibility (MHC)"[https://solvecfs.org/bruno-paiva/].

I'm not sure how Paiva's work fits; HLA's, MHC's, --- it is all quite technical.

In simple terms there is a big segment of a particular chromosome (I think 6) called the Major Histocompatibility Complex (MHC) - which means 'the section where most tissue type genes live.

The MHC was found to be made up of three parts. If I remember correctly they got numbered in the wrong order so that MHCIII is between MHCI and MHCII.

Before this was worked out the tissue type genes (other than blood group ABO etc.) were named HLA (human leucocyte antigen because they are found on nucleated cells like leucocytes). They started out just with numbers as in HLA-3 and HLA-27 but it worked out that all the various tissue type antigen are coded by three genes of one sort HLA-A, HLA-B and HLA-C in the class I section and HLA-D, which turned out to be three also, HLA-DR, HLA-DP and HLA-DQ in the class II section. (It is more complicated but that will do.) The class III section turned out to include genes used for cytokines and complement and not actual tissue type (HLA) antigens if I remember rightly.

All these genes, together with NK killing inhibitor (KIR) and activator receptors tend to vary a lot from person to person so are of great interest in any condition that might involve immunity. I would have thought that if there was anything major to find in ME it would have been found long ago, but I may be wrong.

 

[FMMM1]

In simple terms there is a big segment of a particular chromosome (I think 6) called the Major Histocompatibility Complex (MHC) - which means 'the section where most tissue type genes live.

The MHC was found to be made up of three parts. If I remember correctly they got numbered in the wrong order so that MHCIII is between MHCI and MHCII.

Before this was worked out the tissue type genes (other than blood group ABO etc.) were named HLA (human leucocyte antigen because they are found on nucleated cells like leucocytes). They started out just with numbers as in HLA-3 and HLA-27 but it worked out that all the various tissue type antigen are coded by three genes of one sort HLA-A, HLA-B and HLA-C in the class I section and HLA-D, which turned out to be three also, HLA-DR, HLA-DP and HLA-DQ in the class II section. (It is more complicated but that will do.) The class III section turned out to include genes used for cytokines and complement and not actual tissue type (HLA) antigens if I remember rightly.

All these genes, together with NK killing inhibitor (KIR) and activator receptors tend to vary a lot from person to person so are of great interest in any condition that might involve immunity. I would have thought that if there was anything major to find in ME it would have been found long ago, but I may be wrong.

Thank you very much for your reply; including your views on the likely significance.