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

HLA waiter1
HLA serves up an antigen, ready for a T cell receptor to recognise.

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.

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

HLA molecules help activate T cells

T cells are an important part of the immune system. T helper cells are ‘generals’, co-ordinating the immune system response. For instance, T helper cells play a critical role in firing up antibody-producing B cells and other types of T cell. Killer T cells are more like infantry, acting independently and killing off rogue cells such as those infected with a virus.

But T cells need to be activated first before they get going, and they are activated in part by antigens, which for T cells are peptides, short pieces of protein. And antigens are what HLA molecules are about: they sit on the cell surface and hold out the antigen morsels to the T cells.

If the T cell  receptor recognises the antigen –  in much the same way as an antibody recognises a specific antigen – then that will trigger activation of the T cell. In the case of killer T cells, that’s curtains for the cell doing the presenting – the cell has just signed its own death warrant, but that’s the whole idea.

By taking out the infected cell, the killer T cells are helping to contain an infection and protect other, healthy, cells.

Killer T cells also recognise cancerous cells. And when things go wrong, they can also recognise normal proteins as a threat, leading to autoimmune diseases.

‘Don’t kill me’: HLA class I and killer T cells

Apart from red blood cells and sperm, almost every cell in the body displays class 1 HLA molecules. HLA class I molecules acts as a kind of identity card: it’s the way a cell proves that it is healthy and should be left in peace by marauding killer T cells that will destroy any cell that doesn’t pass muster. You could see killer T cells as an internal security force that’s licensed to kill.

The whole system is pretty elegant and very hard to cheat as the key thing about HLA class I molecules is that they present little bits of whatever proteins the cell that bears them is producing. So if a cell is infected by a virus it will be manufacturing lots of viral proteins, and bits of these foreign proteins end up displayed on the HLA-I molecules. That’s ‘game over’ for the infected cell: once a killer T cell recognises that viral antigen it sends a signal to the infected cell to self-destruct.

So that’s HLA class I: cell-surface molecules that act as identity cards by displaying to killer T cells bits of whatever proteins the diseased cell is making. It’s a way for healthy cells to show that they are ‘clean’, so that the lethal killer T cells leave them alone, while infected cells mark themselves for destruction.

TCR HLA edit
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.

‘Here’s the threat, sort it out’: HLA class II

The other class of HLA molecules, class II, also display antigens, but while class I HLA are on almost all cells , class II are used by the ‘professionals’ – immune-system ‘antigen presenting cells’, such as macrophages, dendritic cells and B cells. Their role is to pick up foreign antigens and present them to other immune cells, particularly T helper cells to kickstart the adaptive immune response. (Adaptive immune responses are very specific, such as antibodies recognising a particular viral protein, as opposed to ‘innate’ responses that recognise classes of pathogens, such as recognising viral RNA or bacterial cells walls.)

Link to Mark Davis’s work on clonal expansion

Once they’ve been primed by class II HLA molecules, T helper cells don’t act directly against an infection. Instead, they help activate other immune cells, including the killer T cells we’ve just discussed and antibody-producing B cells. Killer T cells are the type of cells where Mark Davis has found clonal expansion. When killer T cells are activated (by both T helper cells and the antigen presenting cells) they copy themselves to form an army of clones ready to take on the threat: this is clonal expansion.

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.

(Image credits: Waiter – FreeStockPhotos.biz; HLA/TCR binding – adapted from Elemans et al.)