1. Guest, the 'News in Brief' for the week beginning 16th March 2020 can be found here.
    Dismiss Notice
  2. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

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

Discussion in 'BioMedical ME/CFS Research' started by Sly Saint, Mar 26, 2020 at 12:55 PM.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

    Messages:
    4,226
    Likes Received:
    35,675
    Location:
    UK
    https://www.nature.com/articles/s41598-020-62157-x
     
  2. John Mac

    John Mac Senior Member (Voting Rights)

    Messages:
    222
    Likes Received:
    2,677
    Wouldn't we expect to see much higher differences between the groups if HLA's were involved with ME/CFS?
     
  3. Jaybee00

    Jaybee00 Senior Member (Voting Rights)

    Messages:
    296
    Likes Received:
    1,075
  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    I agree that the difference is modest and not particularly indicative of anything like direct involvement. I also think that adding frequencies for alleles of genes with very different roles is not really legitimate.
     
  5. Simon M

    Simon M Senior Member (Voting Rights)

    Messages:
    283
    Likes Received:
    5,076
    Location:
    UK
    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/
     
    Last edited: Mar 26, 2020 at 6:27 PM
  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    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.
     
  7. Michiel Tack

    Michiel Tack Senior Member (Voting Rights)

    Messages:
    1,601
    Likes Received:
    14,951
    Location:
    Belgium
    Looks like a decent study with large sample size. Would like to see more of these.

    The difference seems rather small, but perhaps it's only relevant to a small subgroup within the ME/CFS population.
     
  8. Grigor

    Grigor Senior Member (Voting Rights)

    Messages:
    111
    Likes Received:
    1,151
    Holy crap.

    "We included 426 ME/CFS patients and 4511 healthy"

    Is that 4511 a typo? Even 451 would be impressive!
     
  9. Chris Ponting

    Chris Ponting Established Member (Voting Rights)

    Messages:
    52
    Likes Received:
    741
    comment copied from Genome-wide association study thread

    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.
     
    Last edited by a moderator: Mar 28, 2020 at 12:49 AM
  10. Marky

    Marky Senior Member (Voting Rights)

    Messages:
    291
    Likes Received:
    2,204
    Location:
    Norway
    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
     
  11. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    2,493
    Likes Received:
    24,312
    If I have DQB1*02 does it mean I can't have DQB1*03:03 or are they two different things?
     
    Invisible Woman likes this.
  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    You will have two copies of the DQB1 gene, one on each of your two chromosome 6s, so you might be 02/03:03 or 02/02.
     
  13. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    2,493
    Likes Received:
    24,312
    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?
     
    Last edited: Mar 28, 2020 at 7:32 AM
    lunarainbows and Michiel Tack like this.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    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.
     
  15. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    2,493
    Likes Received:
    24,312
    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.
     
    Last edited: Mar 28, 2020 at 12:40 PM
  16. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    :thumbup:
     
    Marky likes this.
  17. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    2,493
    Likes Received:
    24,312
    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.
     
    Marky, Michiel Tack and Chezboo like this.
  18. Marky

    Marky Senior Member (Voting Rights)

    Messages:
    291
    Likes Received:
    2,204
    Location:
    Norway
    Good question

    Jonathan will be able to give an professional opinion, but loads of immune dysfunctions are "silent", you only see the aftermath
     
  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    6,434
    Likes Received:
    65,444
    It sounds unlikely to me !
     
    Marky likes this.
  20. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    2,493
    Likes Received:
    24,312
    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?
     
    Robert 1973 and Marky like this.

Share This Page