Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Fluge, Mella et al 2020

strategist said:
How do gradual onsets fit into this? Assuming that they are same illness, or close enough to be indistinguishable other than the initial course of the illness.

Maybe the gradual onset cases have the strongest immune responses so that they can get the illness even without much of a noticable infection. Does that make any sense?

Or immune response could be just one path to the same end result.
Click to expand...

Since many of us worsen over time from moderate to severe, say, it is not a stretch to consider that gradual onset is actually a sudden onset which deteriorates from very mild.

I wonder if hypometabolism could be a protective response to the disease rather than the disease itself. I have deteriorated drastically at times when I lessened my fatigue but the underlying disease continued.
 
Mithriel said:
Since many of us worsen over time from moderate to severe, say, it is not a stretch to consider that gradual onset is actually a sudden onset which deteriorates from very mild.

I wonder if hypometabolism could be a protective response to the disease rather than the disease itself. I have deteriorated drastically at times when I lessened my fatigue but the underlying disease continued.
Click to expand...

I agree

Personally for me it manifested with exercise intolerance with heavy cardio, until one day after football where I just collapsed in the street. Even though it had been gradual before that, pushing over the limit made the worsening sudden. It also means there must have been a sudden disease start anyway prior, right?

"I wonder if hypometabolism could be a protective response to the disease rather than the disease itself."

That does seem pretty likely considering we get PEM after minimal activity
 
Commentary

Summary

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 at least two HLA gene alleles 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 (adaptive) immune system plays a causal role for at least a subset of ME/CFS patients. Though the study is not huge by the standards of these things and the findings need replicating.

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.

HLA waiter1.png
HLA serves up an antigen, ready for a T cell receptor to recognise (sorry pic is so big!)​

Class I HLA proteins - A, B and C - are on the surface of every cell and present peptides to killer (CD8+) T cells. The peptides come from every protein made in the cell. If the cell is only making normal cell proteins, then the peptides resulting from their digestion won't be recognised by any killer T cells. However, if the cell is infected, e.g. by a virus, the killer T cells that recognise the pathogen peptides will be activated and then kill the infected cell. It is a good system.

Class II HLA proteins are a little different (the study only looked at class II alleles of HLA DP1, DQ1 and DR1). These only occur on the surface of "professional" antigen-presenting cells, such as dendritic cells and macrophages. These cells take up suspect pathogens, digest their proteins and present the resulting peptides to T-helper cells (CD4+).

T-helper cells are particularly important because they co-ordinate the immune system. When a T helper cell recognises, say, a viral peptide, it will organise an immune response against the original viral protein. This usually involves activating B cells and killer T cells.

So, class I HLA molecules present to and activate killer T cells which kill infected cells, while class II HLA molecules present to and activate T-helper cells, leading to a coordinated immune response. More information in this blog.

There is a huge amount of variation amongst HLA genes. For instance, there are way more than 100 different alleles of the HLA-A gene, though each person will only have two alleles of each gene. This is important because if a pathogen evolves to bind less well to an HLA molecule, it can evade the immune system. But it’s unlikely to be able to evolve to evade all the alleles in the population of the HLA gene.

Why this is such a good study

This new study by Lande and colleagues of HLA genes is the biggest one by far, with 426 patients diagnosed according to the Canadian consensus criteria, and 4,511 healthy controls. The previous largest study was had 110 cases and all other studies had 58 cases or fewer. The authors sequenced HLA genes enabling them to identify all the different alleles (variants), providing greater accuracy than previous studies. (For example, HLA C allele C*07:04 was significantly associated with ME/CFS, but the other C alleles were not.)

The study uses appropriate corrections for the large number of comparisons, and the main findings even hold up using ultra-strict Bonferroni correction.

Findings The authors found 2 significant HLA associations with ME/CFS. One was tagged by the allele C*07:04 and the other was tagged by HLA-DQB1*03:03. C*07:04 is a class I HLA which presents to killer T cells while DQB1*03:03 is class II HLA interacting with T-helper cells.

However, the situation is more complicated than it seems because other alleles are involved.

Blocks of genes inherited together: haplotypes and linkage disequilibrium
A problem in interpreting the findings of genetic studies is linkage disequilibrium. This clunky phrase simply means that genes that are physically close together tend to be inherited as a block. This block of DNA is known as a haplotype and typically encodes more than one gene.

Even if one allele is associated with a disease, it can be that the biological link is actually with another gene or allele in the same haplotype. Often, further work is needed to identify which gene in the haplotype plays the most important role.

The paper refers to one association being tagged by DQB1*03:03, but it shares a haplotype with HLA B*57:01, the haplotype is referred to as DQB1*03:03-B*57:01. The association for ME/CFS is slightly stronger for DQB1*03:03 (which why it is given the tag status). There is no guarantee that DQB1*03:03 is more biologically important - it could be B*57:01 that plays the key role, or both of them.

Interpretation

DQB1*03:03 is the most interesting association because it is a class II HLA molecule involved in presenting pathogen fragments to fire up T-helper cells and provoke an immune response. Though, as it shares a haplotype with B*57:01, a class I HLA gene, it is possible that the class II molecule isn’t playing an important biological role.

Abnormal immune reaction?
One intriguing possibility, already discussed here on this thread, is that DQB1*03:03 could be linked to an abnormal immune reaction to some pathogens, tying in with the hypothesis that an unusually severe immune reaction to a pathogen as a trigger for ME/CFS. However, the authors point out there is no correlation between self-reported infectious onset and this or any other HLA.

Autoimmunity?
The authors' main interest is autoimmunity and they report higher levels of autoimmune diseases in patients with the significant HLA genes. Autoimmune diseases are often associated with specific HLA genes, but the authors say they are not aware of any reported association between the significant HLA alleles in this paper and the autoimmune diseases reported in their patients. They also say this finding is not conclusive evidence of a role for autoimmunity.

So as far as I can see (and I may be wrong), the only safe conclusion at this stage is that the immune system, via at least two HLA alleles, could cause ME/CFS for at least some patients. But the finding needs replication.
 
Jonathan Edwards said:
There have of course been HLA studies before showing nothing conclusive. I think one suggested a DQ link but it was not confirmed. The UK Biobank data should at least show some signal if either association is real..
Click to expand...
HLA SNPs did not emerge as significant in the two studies to date of over 2,600 people with self-reported CFS in the UK Biobank. However, as the biobank doesn't have full sequences of HLA regions, only SNP genotyping, I don’t think it would have been able to look at all the alleles in the current study, and if so the results would not be comparable.
 
Simon M said:
HLA SNPs did not emerge as significant in the two studies to date of over 2,600 people with self-reported CFS in the UK Biobank. However, as the biobank doesn't have full sequences of HLA regions, only SNP genotyping, I don’t think it would have been able to look at all the alleles in the current study, and if so the results would not be comparable.
Click to expand...

I was thinking of targeted HLA studies further back. I cannot remember details but my understanding is that they were essentially negative. Subtype alleles of traditional HLA numbering would not have been available but I would expect major associations to show through at the traditional level.I agree that there might be linkages to subtype alleles responsible for a shift in threshold for a small proportion of cases - maybe those meeting a particular pathogen. My worry is that if one looks hard enough one is pretty likely to turn up some sort of immune response gene linkage that is relevant to recognition of say EBV and that may not tell us more than we know already - that ME is commonly precipitated by an immune response to something like EBV.
 
Simon M said:
So, class I HLA molecules present to and activate killer T cells which kill infected cells, while class II HLA molecules present to and activate T-helper cells, leading to a coordinated immune response. More information in this blog.
Click to expand...
I’ve just re-read this blog. Very useful. Thanks.

Two questions:

1. If the proposed ME/CFS GWAS study goes ahead, would it be able to confirm whether or not there is an association between these HLA alleles (or any other HLA alleles) and ME/CFS, or would that require whole genome sequencing (or at least full sequencing of HLA regions)?

2. In his blog Simon’s writes: “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.”

If HIV had not been discovered, would the discovery of this HLA gene association with a reduced risk of developing AIDS have helped to point towards the retrovirus as the cause of AIDS? If so, how (in simple terms)?
 
Robert 1973 said:
If HIV had not been discovered, would the discovery of this HLA gene association with a reduced risk of developing AIDS have helped to point towards the retrovirus as the cause of AIDS? If so, how (in simple terms)?
Click to expand...

I think that is very unlikely. We still do not know why HLA-B27 coders protection in HIV, or indeed why it predisposes to the (auto inflammatory) condition of any spond. Paul Bowness in Oxford produced a theory about why B27 is anomalous, relating to its ability to form heavy chain dimers, and I co-authored an Immunology Today review with Paulon the possible mechanisms in around 1990 but thirty years later it is still an open question. A strong possibility is that the protection/risk conferred by HLA-B27 has to do with its binding to natural killer receptors rather than in antigen presentation.

If I remember correctly B27 seems to protect against a range of intracellular pathogens. The simplest story is just that it is 'too good at its job' as a trigger for cellular cytotoxicity. That makes it useful for infections but if you also have a variant of one of the cytokine receptors (IL-17/23) you end up with your cells fighting each other for no reason (Ank spond).

I guess that if we had known more about B27 in 1985 and knew that it protected against AIDS then it might have been reasonable to suggest that AIDS was due to an intracellular infection - but that is about all.
 
Simon M said:
Commentary

Summary

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 at least two HLA gene alleles 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 (adaptive) immune system plays a causal role for at least a subset of ME/CFS patients. Though the study is not huge by the standards of these things and the findings need replicating.

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.

View attachment 10599
HLA serves up an antigen, ready for a T cell receptor to recognise (sorry pic is so big!)​

Class I HLA proteins - A, B and C - are on the surface of every cell and present peptides to killer (CD8+) T cells. The peptides come from every protein made in the cell. If the cell is only making normal cell proteins, then the peptides resulting from their digestion won't be recognised by any killer T cells. However, if the cell is infected, e.g. by a virus, the killer T cells that recognise the pathogen peptides will be activated and then kill the infected cell. It is a good system.

Class II HLA proteins are a little different (the study only looked at class II alleles of HLA DP1, DQ1 and DR1). These only occur on the surface of "professional" antigen-presenting cells, such as dendritic cells and macrophages. These cells take up suspect pathogens, digest their proteins and present the resulting peptides to T-helper cells (CD4+).

T-helper cells are particularly important because they co-ordinate the immune system. When a T helper cell recognises, say, a viral peptide, it will organise an immune response against the original viral protein. This usually involves activating B cells and killer T cells.

So, class I HLA molecules present to and activate killer T cells which kill infected cells, while class II HLA molecules present to and activate T-helper cells, leading to a coordinated immune response. More information in this blog.

There is a huge amount of variation amongst HLA genes. For instance, there are way more than 100 different alleles of the HLA-A gene, though each person will only have two alleles of each gene. This is important because if a pathogen evolves to bind less well to an HLA molecule, it can evade the immune system. But it’s unlikely to be able to evolve to evade all the alleles in the population of the HLA gene.

Why this is such a good study

This new study by Lande and colleagues of HLA genes is the biggest one by far, with 426 patients diagnosed according to the Canadian consensus criteria, and 4,511 healthy controls. The previous largest study was had 110 cases and all other studies had 58 cases or fewer. The authors sequenced HLA genes enabling them to identify all the different alleles (variants), providing greater accuracy than previous studies. (For example, HLA C allele C*07:04 was significantly associated with ME/CFS, but the other C alleles were not.)

The study uses appropriate corrections for the large number of comparisons, and the main findings even hold up using ultra-strict Bonferroni correction.

Findings The authors found 2 significant HLA associations with ME/CFS. One was tagged by the allele C*07:04 and the other was tagged by HLA-DQB1*03:03. C*07:04 is a class I HLA which presents to killer T cells while DQB1*03:03 is class II HLA interacting with T-helper cells.

However, the situation is more complicated than it seems because other alleles are involved.

Blocks of genes inherited together: haplotypes and linkage disequilibrium
A problem in interpreting the findings of genetic studies is linkage disequilibrium. This clunky phrase simply means that genes that are physically close together tend to be inherited as a block. This block of DNA is known as a haplotype and typically encodes more than one gene.

Even if one allele is associated with a disease, it can be that the biological link is actually with another gene or allele in the same haplotype. Often, further work is needed to identify which gene in the haplotype plays the most important role.

The paper refers to one association being tagged by DQB1*03:03, but it shares a haplotype with HLA B*57:01, the haplotype is referred to as DQB1*03:03-B*57:01. The association for ME/CFS is slightly stronger for DQB1*03:03 (which why it is given the tag status). There is no guarantee that DQB1*03:03 is more biologically important - it could be B*57:01 that plays the key role, or both of them.

Interpretation

DQB1*03:03 is the most interesting association because it is a class II HLA molecule involved in presenting pathogen fragments to fire up T-helper cells and provoke an immune response. Though, as it shares a haplotype with B*57:01, a class I HLA gene, it is possible that the class II molecule isn’t playing an important biological role.

Abnormal immune reaction?
One intriguing possibility, already discussed here on this thread, is that DQB1*03:03 could be linked to an abnormal immune reaction to some pathogens, tying in with the hypothesis that an unusually severe immune reaction to a pathogen as a trigger for ME/CFS. However, the authors point out there is no correlation between self-reported infectious onset and this or any other HLA.

Autoimmunity?
The authors' main interest is autoimmunity and they report higher levels of autoimmune diseases in patients with the significant HLA genes. Autoimmune diseases are often associated with specific HLA genes, but the authors say they are not aware of any reported association between the significant HLA alleles in this paper and the autoimmune diseases reported in their patients. They also say this finding is not conclusive evidence of a role for autoimmunity.

So as far as I can see (and I may be wrong), the only safe conclusion at this stage is that the immune system, via at least two HLA alleles, could cause ME/CFS for at least some patients. But the finding needs replication.
Click to expand...

Thanks for this.

Where is the HLA/antigen image from? I didn't see it in the publication.
 
Simon M said:
HLA SNPs did not emerge as significant in the two studies to date of over 2,600 people with self-reported CFS in the UK Biobank. However, as the biobank doesn't have full sequences of HLA regions, only SNP genotyping, I don’t think it would have been able to look at all the alleles in the current study, and if so the results would not be comparable.
Click to expand...
. My gentle wonderings and it would be lovely to get more background information to help me make sense of stuff :-
1) Will there ever be a deep dive into the sequences of the HLA regions of these 2600 self reported CFS patients in UK Biobank as these technologies get ever cheaper?
2) Will the self reported CFS cases ever be properly diagnosed?
3) How were the 100,000 people chosen to be in the Genomics England 100,000 genome project? Are these the same people in the UK Biobank?

As you can see I'm quite confused?

Very interesting though.
 
Main author Asgeir Lande has written a comprehensive summary of the study for the Norwegian ME Association

The HLA association we found in our study is not as strong as for many established autoimmune diseases. The results should also be repeated in other patients before we can assume that they are true for ME patients in general. The fact that the alleles are present only in a subgroup of patients, however, is quite typical of autoimmune diseases. It may be that certain alleles increase the risk of developing a particular disease, without the alleles being sufficient causes in themselves. Whether this applies to ME is thus still uncertain, but our findings indicate that the immune system is involved in the development of ME.

In the first place, our findings cannot change neither the diagnosis nor the treatment of ME. But the study is a piece of the puzzle that needs to be put in order to better understand the disease.

Asgeir Lande: HLA-gener og ME
google translation: HLA-genes and ME
 
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00612/full

Inheritance of HLA-Cw7 Associated With Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual’s immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features.
Click to expand...


From Wikipedia--Cw7 serotype: C*07:01 to *07:06, *07:12, *07:14, *07:16


Something is going on here. I am not a geneticist--I guess that F & M used mol. genetics and this paper used serotyping--would be interesting to know if these authors could drill down to the next level (specific allele protein) to see if HLA-C*07:04 is involved with autism.









 
Jonathan Edwards said:
Yes, if the association is confirmed it will indicate that somewhere along the long presentation of antigen to helper CD4 T cells is involved and that pretty much indicates that antibody production is involved since that is what CD4 T cells help B cells to do.

BUT, remember that we are already pretty sure that a significant proportion of ME/CFS follows an acute febrile reaction to a virus. That involves CD4 helper T cells and antibody production so in a sense a DQ link is completely unsurprising. Genes like DR and DQ were originally called Ia (immune associated) or IR (immune response) genes because the various different alleles confer different levels of immune response to viruses or bacteria (at least in mice). DQ 03:03 might confer a rather strong response to EBV for instance. So it might confer risk for ME following EBV. It does not need to indicate any sort of autoimmune process, or indeed any ongoing immune process after an initial reaction to a microbe.
Click to expand...


which would also mean damage is most likely of permanent nature.
 
First author of this study, Asgeir Lande, will next week be defending his thesis "Human leukocyte antigen associations in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and immune modulating treatment".

The defence is digital and public.

More information:
https://www.med.uio.no/klinmed/engl...ts/events/disputations/2021/lande-asgeir.html


Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and complex disease characterized by medically unexplained chronic fatigue, post-exertional malaise and a variety of additional symptoms. The etiology is unknown, and many different disease mechanisms have been proposed. Several immunologic changes have been reported among patients in different studies. A central hypothesis is that autoimmunity is involved in the pathogenesis of ME/CFS.

Autoimmune diseases (AID) are complex diseases with large variation in symptoms and severity. Genetic associations with the immunologically important human leukocyte antigen (HLA) genes are hallmarks of AID, typically manifested by a higher prevalence of specific HLA risk alleles among patients.

The main aim of this thesis was to evaluate the hypothesis that autoimmunity is involved in ME/CFS pathogenesis. First, we wanted to conduct a large and high resolution genetic HLA association study in ME/CFS. Next, we wanted to assess safety and potential effect of the immunosuppressive agent cyclophosphamide in a smaller group of ME/CFS patients. Finally, we wanted to see whether potential HLA risk alleles were associated with questionnaire-based clinical information or therapeutic effect.

We identified two novel HLA associations for adult, Norwegian ME/CFS patients, represented by a significantly higher prevalence of the alleles HLA-C*07:04 and HLA-DQB1*03:03 among 426 patients than among 4511 healthy controls. 22 out of 40 patients reported substantial clinical improvement after receiving cyclophosphamide, but the results must be cautiously interpreted since there was no control group. The HLA risk alleles were further significantly associated with comorbid autoimmunity among patients, and with clinical improvement after cyclophosphamide treatment.

Our results are in favor of immunological involvement in ME/CFS pathogenesis, possibly in a subgroup of patients, but the results need to be reproduced in additional studies before they can be regarded as established.
 
You must log in or register to reply here.
Back
Top