Ron Davis: Grant award: Molecular and single-cell immunology in ME/CFS

Good point. There’s a lot of time and resources being ploughed into this hot topic by some excellent researchers. That’s not so unusual in many fields. Wouldn’t it be great if it became commonplace for ME/CFS research?

 

I am curious how they won this funding, i didn't know they had a pending NIH application. Do they have more applications pending?
Not that i am complaining in the slightest.

 

I don't think we have been told enough to know if or how the metabolic trap hypothesis and the T cell and HLA work might fit together. They may be different subsets.

Regarding Phair's work, I think the idea is that certain gene mutations are potentially involved in giving rise to (a tendency to) metabolic processing errors:

https://www.omf.ngo/2018/03/14/omf-funded-research-a-metabolic-trap-hypothesis-for-me-cfs/

Ron (also) mentioned the KIR locus as being of interest in the SIPS (Severely Ill Patient Study) in the OMF update at the end of last year.

A bit of basic background for anyone, like me, who is learning as they go along with this stuff:

The HLA locus is a group of genes that codes for, or contains the construction blueprint for, a set of proteins called the major histocompatability complex, or MHC.

The main role of the MHC proteins is to bind to antigens, or the unique proteins found on the surface of a pathogen, and present them to T cells, in order to provoke the T cells into replication, or clonal expansion, to deal with the threat. This kind of T cell response is what Mark Davis has found, and what Chris Ponting hopes to replicate (or not).

KIR is an acronym for killer-cell immunoglobulin-like receptors, and these receptors are found on natural killer, or NK, cells, and a few T cells. NK cells target problematic self-molecules and either destroy them or cause them to commit suicide. For example, they target virally infected cells (as opposed to directly attacking the virus itself, which is the job of the T cells).

MHC molecules also interact with KIRs to regulate the killing activity of NK cells. Most KIRs are inhibitory, so they down-regulate killer cell activity. They are one of the keys to self-defence without self-destruction: if all goes well, only dangerous cells should be killed, not healthy ones.

Combinations of KIR and HLA genes have been associated with various autoimmune diseases, and with viral infections.

So as a very broad brush, the HLA genes are instrumental in the immune response aimed directly at pathogens (as part of the adaptive immune response), and the KIR genes are particularly relevant in defending against things that have co-opted self cells, eg cells infected with a virus, or cancerous cells, as part of the innate immune response.

 

According to Cort's article about this on his website ( https://www.healthrising.org/blog/2018/06/25/davis-nih-grant-chronic-fatigue-syndrome/), it seems that this was the first of Ron Davis' applications to go through a "special emphasis" review panel for ME/CFS.

 

Interesting, thanks
I'm glad they got it, and i hope they keep applying for more since OMF is chasing many leads.

 

Just FYI, Ron did mention this application just after he was turned down for the research collaborative centre grants.

 

cool, i missed or forgot about that

 

OMF: HealthRising: Ron Davis (Finally) Gets His Big Grant!

https://www.omf.ngo/2018/06/26/davis-nih-grant/

June 26, 2018

This #OMFScienceWednesday we share the exciting news that Dr. Ron Davis and his team have received an NIH award for 5 years, $3.9 million total grant of which $2.5 million goes to research and the rest goes to Stanford University overhead. (NIH always pays universities their “overhead or indirect” costs on top of the grant amount that was applied for.)

The grant is to study the “Molecular and Single Cell Immunology of ME/CFS.” Thank you Cort Johnson for writing this wonderful article to explain the grant.

by Cort Johnson

“This proposal aims to uncover the immunological basis of ME/CFS”. Ron Davis – Grant application

Sometimes the third time is the charm. Ron Davis has gotten (and been turned down for) many NIH grants but even he was shocked by the response to his first couple of attempts to get an NIH grant for chronic fatigue syndrome (ME/CFS)...

 

@Simon M has written a blog on this news

https://mecfsresearchreview.me/2018...mune-study-is-looking-at-hla-genes-heres-why/

 

I wonder if we are seeing Mark Davis's influence here. He would be very familiar with the HLA connection to Allen Steere's theory about the origin's of arthritis refractory to treatment in some Borrelia cases.

That is a very specific HLA connection, of course - HLA-DR4 - and presumably there are countless others, but for me it is an interesting development nevertheless.

This is not trying to take something away from Ron Davis's own brilliance and initiative.

 

OMF have posted a video of Ron Davis talking about the new grant:

https://www.youtube.com/watch?v=eQR4zpiyE6I

 

Interesting video, worth a 5 min watch.

A few things that struck me:
1. Mark Davis is joing Principal Investigator along with Ron Davis, which probably isn't surprising given that MD is the immunology expert.

2. Bit more about HLA (see my blog on this)
They will use new technology to sequence HLA genes, developed by another group who will be part of this new project. The new tech is already in use commercially, and is used by Stanford in its transplant work.

[That might seem odd, but HLA genes were discovered because, it turns out, that if you have different HLA genes (and so different HLA proteins) from the organ donor, your body will reject the new organ. Hence the need to "tissue match" potential organ donors with recipients. This rejection role of HLA is separate from its main role in activating T cells and other parts of the immune system.]

3. They will use more sensitive sequencing to search for possible pathogens in the blood (previous work has drawn a blank, their work and those of others inc Ian Lipkin).

4. The goal is to find out what's driving the T cell clonal expansion. Apart form pathogens, it could also be autoimmunity driving clonal expansion.

Ron Davis mentioned a 3rd possible driver for T cell clonal expansion: non-specific activation of the immune system.

@Jonathan Edwards mentioned something like this before (in psoriasis?) and would be the best person to comment; I'm not sure of the details.

 

HLA is on the short arm of chromosome 6 could any other genes in that area be of interest I wondered
Is HLA too obvious a place to look and has it been looked at before

 

whatever happened to the 'mystery molecule' Rons team found ages ago but couldn't identify?

( @JaimeS I think it might have been around the time when you started at Stanford.)

 

Ron Davis mentioned a 3rd possible driver for T cell clonal expansion: non-specific activation of the immune system. @Jonathan Edwards can you explain briefly what non specific activation of the immune system is and what diseases display this?

 

I must say I liked listening to Ron Davis "the scientist" . Hopefully we will have more of these videos coming in the future.

Another thought : What could we do to try to speed up the research of T cell clonal expansion drivers. Does it only depends on money ?

 

Replication - hence importance of Chris Ponting' s research.
Outcomes during/ from this study may also drive replication necessity for other aspects.

It may help give a direction for future research areas - important when proposals are invited for funding.

 

Thanks Simon.
This particular point is certainly of interest to those of us who have a strong family pattern of autoimmune disease.

 

I think I need a little context for this?