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

New blog at ME/CFS Research Review

Dr Ron Davis has won a large NIH (US National Institutes of Health) grant for an immunology project with a strong focus on HLA genes. Which may have led some to wonder, ‘What are they?’

HLA (human leukocyte antigen) molecules play a critical role in the immune system, particularly by activating T cells. There is a huge amount of variation in the HLA genes that different people have, and Davis’s theory is that certain types of HLA genes could increase the risk of ME/CFS.

The following explanation of HLA molecules is taken from a piece I wrote a few years ago.

The short version
HLA molecules fire up T cells

T cells play a key role in the immune system. Like antibodies, the receptors of T cells respond to very specific antigens (foreign proteins), much like a lock matching just one key.

However, while antibodies will recognise and bind to part of a whole protein, such as the protein coat of a virus, T cell receptors only recognise tiny fragments of proteins. And T cell receptors can’t respond to antigens unless they are presented in just the right way.

​

HLA serves up an antigen ready for a T cell to recognise.​

That’s where HLA molecules come in. At a very basic level, HLA molecules act like waiters, serving up the antigen on a plate. More precisely, HLA molecules – which sit on the cell surface – have a groove that cradles the small antigen, and the T cell receptor binds to the antigen and HLA molecule together.

If the T cell receptor recognises the antigen proffered by the HLA molecule (strictly speaking, several different molecules combine to make an HLA complex) then the T cell will snap into action. But without HLA molecules, T cells wouldn’t be able to take action against threats to the body.

HLA in ME/CFS and other diseases
We have six different types of HLA molecule that present to T cells, and there are many different versions of each of the six types. Ron Davis at Stanford believes that the version of HLA genes you have may influence the risk of getting ME/CFS, and certainly HLA gene variants have been linked to numerous diseases. One particular version of an HLA gene increases the risk of narcolepsy by 130 times. A version of another HLA gene conveys some protection against HIV developing into AIDS – though the same gene variant increases the risk of the autoimmune disease ankylosing spondylitis. In fact, HLA genes are linked to a number of autoimmune diseases.

More about the biology (it’s fun, really!)

read the full blog​

 

Thanks for making this understandable

 

As I mentioned in the other Ron Davis thread, I cannot help but notice the link an HLA theory would have to an area Mark Davis is well-versed in, so I wonder if we are perhaps seeing his influence here, at least a bit.

 

That was a really helpful and clear description. Brilliant. Thank you Simon.

So million dollar question.......will Chris Ponting be trying to replicate Ron Davis's work? Using the ME Biobank samples perhaps?

I so much hope so.

 

Thanks for the blog Simon, very readable.

Spotted a couple of things that you might want to look at:
This one's pretty minor. Where you say "Ron Davis at Stanford believes that the version of HLA genes you have may influence the risk of getting ME/CFS, and certainly HLA gene variants have been linked to numerous diseases.", the linked text is in two sections, and the "i" from influence isn't part of the link. Weirdly though it has copied across to here as one link, so it may be a Wordpress formatting thing.

And you have a section heading of "MHC molecules help activate T cells" but then don't mention MHC molecules until two sections later, under the heading "Link to Mark Davis’s work on clonal expansion", "Once they’ve been primed by class II MHC molecules, T helper cells don’t act directly against an infection.". Did you mean to have some text explaining what MHC molecules are in there somewhere?

 

The biobank sample is currently too small (it probably needs 1,000 patients or more) and HLA genes are hard to sequence for technical reasons. Ron has invented a new sequencing method that he will apply in his new study.

Thanks. I had to sort out the risk link gremlin in the source code!

Whoops! MHC stands for major histocompatability complex; "histocompatability" is all about tissue matching - and the problem of organ/graft rejection. MHC was discovered by accident through this, and studied in mice, where the relevant genes were named MHC. The equivalent human genes to MHC were called HLA. I'd meant to switch all MHC references in my original piece to HLA, but missed some. Blog now fixed.

While I think of it, here are some social media links if anyone would like to share

https://twitter.com/user/status/1012277735614504960




(Thanks to @Andy or whoever at s4me has shared already.)

 

Thank you so much @Simon M for your always great explanations.

What could be the implications of the HLA possible findings in terms of treatments? I always dream of it.

Almost one year ago we knew about Mark Davis T cell research and the possibility of at least one internal antigen . When do you think we will have the confirmation of this finding. Why Science seems so slow?

 

If there is a link between HLA and ME/CFS it wouldn't directly leads to to treatment. However, if HLA are shown to be a risk factor, that would point strongly to an infectious or autoimmune cause. It is possible the finding would help researchers to track down the specific infections/autoimmune trigger, but I don't know.

It takes time to do science well. In this case, the technology being used is cutting edge and still under development. Davies has said the work could well take several years. That’s partly because it is incredibly difficult to do, and I suspect the technology isn’t quite there yet either. Which doesn’t necessarily make it any less frustrating for patients.

 

@Simon M when did Davis say it could take several years?....I remember last May in my desperate state I emailed Janet Dafoe and I asked if we would have treatment within 10 years. .she qouted Ron as saying that he anticipated we would find something much sooner than that. But that was last May and maybe that was being over optimistic. I'm not sure how to interpret several years....if it's autoimmune...as it must be at least for a cohort as multiple family members can have it...why would it take so long to find that as we have so many autoimmune diseases already...sorry, feeling a tad frustrated

 

@Simon M Thank you for your answer and for your patience!!!!

 

Interesting article on how the cytomegalovirus (CMV) evades the immune system. It prevents the infected cell's MHC (HLA) molecules from reaching the surface of the cell, where they would normally prompt the immune system to destroy the cell. However, the absence of MHC molecules on the cell's surface would also be a signal to the suspicious immune system to destroy the cell. So - CMV has evolved a way to build phony MHC molecules that look innocuous to the immune system (even though they are quite different from actual MHC molecules).

I could be wrong, but I'd assume that the infected cells would still release CMV into the blood stream. Presumably, the immune system would recognize and destroy these viruses, but it wouldn't be able to find the source (the infected cells) and eliminate it.

https://www.sciencedaily.com/releases/2008/07/080718085117.htm

 

I remember Janet telling everyone on PR she was sure we'd have something by last Christmas. Since then I've taken her predictions with a pinch of salt. I really don't mean to start a discussion about PR or Janet, but I think it's important that the issue of giving false hope is addressed openly, if it's resulting in desperate sufferers feeling frustrated when those hopes don't materialise.

 

I do agree. It's hard to know where we stand really... there is a bit of that false hope with the metabolic trap theory also. I know Linda Tannenbaum said that she truly believed we would have treatments within next 5 years. Great to hear at the time but not so great when u start realizing that it's probably unlikely. I was also told by another member of OMF that we would probably know if ME was an autoimmune disease or not in a year's time (this was said last month)...now @Simon M is saying several years....and that is what a 5 year grant indicates. It's like some one messing with your head... no matter how many times it happens, the disappointment still hits me hard.

 

Agree with everything said but would add:
I am not sure if there is a direct link between the duration of a grant and a breakthrough discovery.

5 years is probably a very common grant duration and I am sure Ron Davis would have applied for the longest duration available to ensure continuity of funding.

There is a lot happening but making any prediction on timelines is just too difficult.

 

Seems like hla-c*07:04 is a predictor of response to cyclo. It is very premature, but how does one test to figure out if ones got this or not?

 

I've done pre-transplantation blood work (HLA typing) on dialysis patients.

HLA of donor and recipient patient have to be the same (to "match") otherwise immediate organ rejection happens.

Nice to hear more about HLA system.