ME/CFS Research review blog post, by Simon McGrath, 28 June 2018: Dr Ron Davis’s big immune study is looking at HLA genes – here’s why

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.

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…

A killer T cell in action against a cell infected by a virus. An HLA class I molecule offers up a viral antigen, and a T cell with a matching receptor binds to the HLA molecule and the antigen together. The T cell responds by killing the infected cell.

Back to the Ron Davis study: HLA and disease

There are three types of class I HLA molecules (HLA-A, HLA-B and HLA-C) – and three important types of class II HLA molecules (HLA-DP, HLA-DQ and HLA-DR). That makes six types, but there are huge numbers of different versions of each type.

Different versions of HLA are associated with increased risk (or even decreased risk) for certain diseases, particularly autoimmune diseases.

In 2014 Ron Davis reported that initial HLA profiling of 400 individuals indicated that patients had different versions of the genes that encode the HLA protein from healthy people – but that they needed to profile more people to confirm this finding. A new study that has just been announced should establish if particular versions of HLA molecules increase the risk of getting ME/CFS.

The project starts this month and is expected to complete by 2023. More information about the study at Health Rising.

Read Simon McGrath’s full article

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