Human leucocytes Antigen (HLA) proteins play an essential role in helping the immune system to recognise pathogens. This new research is easily the best study yet of HLA alleles (gene variants) in ME/CFS. It finds links between alleles of at least two HLA genes and ME/CFS. And since the illness can’t change (HLA) DNA, the link must be that the alleles must play a causal role in ME/CFS. So this evidence that the immune system plays a causal role for at least a subset of ME/CFS patients. The finding needs replication.

Does ice cream cause sunburn? The evidence for this is that many people who buy ice cream also get sunburn. Of course, ice cream doesn’t cause sunburn, people buy ice cream and get sunburn on sunny days. But this illustrates a problem faced by researchers: just because two things occur together is no guarantee that one causes the other.

Take the example of cytokines, immune messenger molecules, in ME/CFS. Researchers have found abnormalities in the level of several cytokines, which could be evidence that problems in the immune system are driving ME/CFS. Equally, the cytokine abnormalities could simply be the result of ME/CFS or just a general effect of being ill.

However, genetic studies provide a solution to this cause-or-effect problem. When genetic differences are linked to an illness, it is evidence that the gene differences play a causal role. The reason is that we are born with our genes and ME/CFS develops much later: since genetic differences come first they must play a role in causing the illness. In any case, because DNA can’t be changed (with few exceptions) the reverse is not true, the illness cannot cause the genetic differences.

A new genetic study has found that alleles of at least two immune system genes are linked to ME/CFS. This is the most convincing evidence yet that a problem in the immune system is driving ME/CFS, at least for some people.

The research, from a Norwegian team including Dr Oystein Fluge and Professor Olaf Mella, is the largest published study of immune system genes to date. It had 458 patients (meeting Canadian consensus criteria) and 4,500 controls. The study also used a more sophisticated approach than similar studies.

HLA alleles associated with ME/CFS. Lande, 2020

The researchers looked at genes for one part of the immune system, human leucocytes antigens (HLA). HLA genes make proteins that are essential for the immune system to recognise different pathogens.

The biology of HLA

HLA are cell surface molecules that present peptides, digested fragments of proteins, to the T cell receptors (TCR) of T cells.

This leads to some T cells killing infected cells and other T cells organising an immune response against microbes.

There is a huge amount of variation amongst HLA genes. For instance, for many genes, there are only a couple of different versions of the gene in the population (each version of a gene is called an allele).   But there are way more than 100 different alleles of the HLA A gene in the population, though each person can only have two alleles of each gene.

This variety is important because if a pathogen evolves to bind less well to an HLA molecule, it can effectively hide from the immune system. But with many versions of each HLA gene, a pathogen is unlikely to be able to evolve to hide from all the versions of the HLA molecule in the population and most people will be OK.

The researchers took an unusual approach by sequencing HLA genes, which allowed them to identify all the different gene variants. Earlier studies of HLA genes were only able to identify some of the alleles, or look at groups of alleles together – meaning they could miss important differences.

Findings

The study found 2 pairs of HLA alleles were linked to ME/CFS. One pair includes HLA a D and B alleles (DQB1*03:03-B*57:01). The other pair includes a C and a B allele, (C07:04 and B 44:02).

Although these alleles were more common in patients than in controls, most patients did not carry any of them:

• C allele: patients, 7.7%; controls, 3.8% of controls
• D allele: patients, 12.7%, controls, 8.7%

But then it’s no surprise that ME/CFS isn’t caused by just one or two genes – if it was, the genes would have been found by now. Instead, these results indicate the alleles could play a small role for a lot of people, increasing the risk of ME/CFS. Or play a bigger role for a subgroup of patients.

The reason the study found pairs of alleles is because of how we inherit DNA. When two genes are very close together, separated by only a short stretch of DNA, they are usually inherited together. In the case of the pairs here it means that if you have the specific allele of HLA D, you will almost always have inherited a particular allele of HLA B.

So it isn’t possible to say which gene in the pair is playing a role in causing ME/CFS. More research would be needed to identify which gene is biologically important. Life is never simple.

What the findings mean

Abnormal immune reaction?

The involvement of an HLA D allele is particularly interesting because it is involved in presenting pathogen fragments to fire up T helper cells and provoke an immune response. So its role might be to cause an abnormal immune reaction to some pathogens. This ties in with the idea that an unusually severe immune reaction to a pathogen leads to ME/CFS. However, the D allele wasn’t any more common in patients whose illness started with an infection, which argues against a link to infections.

Autoimmunity?

The researchers are experts in autoimmunity and so looked at the levels of autoimmune diseases in patients. The found that who had these HLA alleles were more likely to have autoimmune illnesses than those who did not. However, the authors said that this finding alone cannot prove that autoimmunity plays a role in ME/CFS.

From my perspective, all we can safely say at this stage is that the immune system, via at least two HLA alleles, could cause ME/CFS for at least some patients. And that’s important. What’s needed now is a replication to check the findings are robust.

A Ron Davis replication?

In 2018 Ron Davis won an NIH grant that allows him to complete an earlier HLA gene study that showed promising results. So it appears that a replication is in progress.

If these findings do replicate then I think the HLA gene findings will prove to be important, firmly indicating that the immune system plays a role in driving ME/CFS, rather than simply being changed as a result of the illness.

Follow @sjmnotes

Image credits: HLA waiter, FreeStockPhotos.biz; T cell, favpng; T cell electron micrograph, NIAID;