How does the HLA locus fit into the metabolic trap hypothesis ?
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:
OMF said:
The big data study of severely ill ME/CFS patients that we funded identified several genes that carry damaging mutations. Dr. Phair’s hypothesis, based on computational predictions, suggests that some of these mutations may slow down enzymes that process important metabolites required for our energy, brain function, and immune system. If this is true, it could explain some of the symptoms of ME/CFS. Identifying interesting mutations is the (relatively) easy part, though – experimental evidence is needed to confirm their impact. During this project, the team will test how cells with these mutations carry out the relevant metabolic reactions, using special ‘tracer’ metabolites that can be easily followed as they are processed by the cells. These experiments will determine whether the mutations are indeed creating a metabolic ‘trap’ that could lead to the neurological and/or immunological symptoms of ME/CFS.
https://www.omf.ngo/2018/03/14/omf-funded-research-a-metabolic-trap-hypothesis-for-me-cfs/
I think Ron said at LiME 2017 that HLA sequence showed interesting results in severely ill patients
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.
