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

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Abstract


The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.
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https://www.nature.com/articles/s41598-020-62157-x
 
Yes, it’s a modest effect size, but there is correction for multiple comparisons (how nice to see). It could be a signal related to autoimmune and/or infectious subgroups.

Ron Davis is also looking at HLA genes, so there should be a replication on the way


“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.”

https://mecfsresearchreview.me/2018...mune-study-is-looking-at-hla-genes-heres-why/
 
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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.

I would caution strongly against lumping these two associations together as 'a signal' indicating anything. HLA-DQ and HLA-C have pretty unrelated roles and I know of no autoimmune disorder with twin links of this sort. Lupus has a link to a haplotype that involves A, B and D loci if I remember correctly but that seems to be a linkage disequilibrium effect. I think the two associations should be treated each on their merits alone. C 0704 is an odd one I have not seen come up before, but I am about ten years out of date on that.
 
comment copied from Genome-wide association study thread

Kalliope said:
Prof. Benedicte A. Lie is also a co-author of the recent Nature study "Human Leukocyte Antigen alleles associated with ME/CFS" from among others Fluge and Mella.
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Small study, but great to see a genetic signal. This needs replication and more samples, but at the moment this does point towards an adaptive immune contribution to ME. Encouraging.
 
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Looks like solid work again from Fluge & Mella, especially the sample size :emoji_clap:

They say: "A dysregulated activity of CD4 positive T lymphocytes, the principal cell type interfering with HLA class II alleles, have been discussed as a central mechanism in ME/CFS (42)"

Maybe I should ask them about one of my random lab findings: "Approximately 33 % of the CD4+ T-lymphocytes are CD45RA and CDRO double positive. This finding has uncertain meaning, and should be controlled with new tests at a later time."

From what i read on double positive CDRO and Cd45RA its suspected to be connected with autoimmunity.. I always wondered if other ME-patients have this
 
Is it right to say that assuming the HLA-DQB1 association is true, it would mean that the disease process in ME/CFS at least in some patients involves antigen presentation by B lymphocytes, dendritic cells, macrophages, and T cells reacting to these antigens? At least that's what Wikipedia says about the role of DQB1.

Is it possible that self-targeted antibodies are occurring only early on in the illness and that is why B cell depletion does not work?
 
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strategist said:
Is it right to say that assuming the HLA-DQB1 association is true, it would mean that the disease process in ME/CFS at least in some patients involves antigen presentation by B lymphocytes, dendritic cells, macrophages, and T cells reacting to these antigens? At least that's what Wikipedia says about the role of DQB1.

Is it possible that self-targeted antibodies are occurring only early on in the illness and that is why B cell depletion does not work?
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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.
 
The narrative could then be: since the severity of infection predicts subsequent ME/CFS in at least one prospective study that would be consistent with the severity of the immune response being an important factor, which depends in part on genetics. It might not be about the infection per se but about the immune response, and consistent with that interpretation is also the observation that a wide variety of pathogens can apparently cause ME/CFS or at least a family of postinfectious illnesses that have great overlap.
 
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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.
 
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.
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Good question

Jonathan will be able to give an professional opinion, but loads of immune dysfunctions are "silent", you only see the aftermath
 
Okay, another question:

There is this idea that cells in ME/CFS cells have entered a hypometabolic because they feel threatened by something (in the blood).

This is maybe not yet a cast iron fact but let's assume that it's true.

Is this a recognized response tied to the innate immune system? The adaptive immune system? Or a different response alltogether that doesn't have much to do with the immune system, perhaps because it's an evolutionary ancient response that predates the immune system?
 
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