Immune exhaustion in ME/CFS and long COVID, 2024, Eaton-Fitch et al.

Discussion in 'ME/CFS research' started by SNT Gatchaman, Oct 22, 2024.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Immune exhaustion in ME/CFS and long COVID
    Natalie Eaton-Fitch; Penny Rudd; Teagan Er; Livia Hool; Lara Herrero; Sonya Marshall-Gradisnik

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently.

    RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18). Participants with ME/CFS were included according to Canadian Consensus Criteria. Participants with long COVID were eligible according to the case definition for “Post COVID-19 Condition” published by the World Health Organization. RNA was analyzed using the NanoString nCounter Immune Exhaustion gene expression panel.

    Differential gene expression analysis in ME/CFS revealed downregulated IFN signaling and immunoglobulin genes, and this suggested a state of immune suppression. Pathway analysis implicated dysregulated macrophage activation, cytokine production, and immunodeficiency signaling. Long COVID samples exhibited dysregulated expression of genes regarding antigen presentation, cytokine signaling, and immune activation. Differentially expressed genes were associated with antigen presentation, B cell development, macrophage activation, and cytokine signaling.

    This investigation elucidates the intricate role of both adaptive and innate immune dysregulation underlying ME/CFS and long COVID, emphasizing the potential importance of immune exhaustion in disease progression.

    Link | PDF (JCI Insight) [Open Access]
     
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  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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  3. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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  4. forestglip

    forestglip Senior Member (Voting Rights)

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    I'm a bit confused about whether the HLA genes are differentially expressed in ME/CFS. That statement seems to say so, but Figures 2 and 3 don't show those genes being significant.
     
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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Well, that's confusing. Looking at the raw data (normalised counts) from supp file 1 and reordering/transposing —

    For HLA-DQA1
    HC01 10.6659423
    HC02 9.7885739
    HC03 11.2015097
    HC04 10.3171179
    HC05 11.8322613
    HC06 11.3585728
    HC07 3.23962947
    HC08 9.95662161
    HC09 12.0608293
    HC10 2.33747648
    HC11 11.5315697
    HC12 11.5688589
    HC13 2.56401497
    HC14 11.251918
    HC15 10.2873327
    HC16 10.3869218
    HC17 11.1585409
    HC18 10.8374035

    LC01 9.55748782
    LC02 10.3496759
    LC03 1.82308287
    LC04 11.540439
    LC05 2.50327065
    LC06 3.82728498
    LC07 3.17607999
    LC08 11.0519093
    LC09 5.03855048
    LC10 2.53558357
    LC11 1.77570456
    LC12 3.10386832
    LC13 10.5981617
    LC14 3.06462539
    LC15 11.3712974

    ME01 10.5853984
    ME02 2.07604557
    ME03 10.0873391
    ME04 2.99365564
    ME05 10.5596958
    ME06 3.30327988
    ME07 9.85769108
    ME08 11.3484699
    ME09 11.3198184
    ME10 0.76455194
    ME11 2.5244207
    ME12 10.640375
    ME13 2.76768527
    ME14 2.69310125

    For HLA-DQB1

    HC01 10.6659423
    HC02 9.7885739
    HC03 11.2015097
    HC04 10.3171179
    HC05 11.8322613
    HC06 11.3585728
    HC07 3.23962947
    HC08 9.95662161
    HC09 12.0608293
    HC10 2.33747648
    HC11 11.5315697
    HC12 11.5688589
    HC13 2.56401497
    HC14 11.251918
    HC15 10.2873327
    HC16 10.3869218
    HC17 11.1585409
    HC18 10.8374035

    LC01 9.55748782
    LC02 10.3496759
    LC03 1.82308287
    LC04 11.540439
    LC05 2.50327065
    LC06 3.82728498
    LC07 3.17607999
    LC08 11.0519093
    LC09 5.03855048
    LC10 2.53558357
    LC11 1.77570456
    LC12 3.10386832
    LC13 10.5981617
    LC14 3.06462539
    LC15 11.3712974

    ME01 10.5853984
    ME02 2.07604557
    ME03 10.0873391
    ME04 2.99365564
    ME05 10.5596958
    ME06 3.30327988
    ME07 9.85769108
    ME08 11.3484699
    ME09 11.3198184
    ME10 0.76455194
    ME11 2.5244207
    ME12 10.640375
    ME13 2.76768527
    ME14 2.69310125
     
  6. forestglip

    forestglip Senior Member (Voting Rights)

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    My best guess is something like, by themselves, the HLA genes weren't significantly different, but when combined with the other genes that make up a pathway, the combination/pathway was significant: "overlapped with ME/CFS with the addition of IGHG3, CCL2, CEACAM3, and IFNA6."
     
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  7. forestglip

    forestglip Senior Member (Voting Rights)

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    100% of ME/CFS and 73.3% of LC had PEM.

    I think the genes/pathways most likely to be important would be the ones significant in both LC and ME/CFS, so here are the parts that they have in common:

    Gene expression
    Downregulated
    IGHG1
    IGHG2
    IGHG3
    IGHG4

    Upregulated
    CEACAM3
    PIK3R1
    TNFAIP3
    Screenshot_20241022-220519.png

    Some other interesting bits:
     
    Last edited: Oct 23, 2024
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  8. forestglip

    forestglip Senior Member (Voting Rights)

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    I mean significant by themselves in long COVID, but only significant in combination with other genes in ME/CFS, is my interpretation of that sentence.

    Edit: I think those significant combinations in ME/CFS that include HLA are in Table 6: activation of leukocytes and activation of antigen presenting cells.
    jci.insight.183810.t6.jpg
     
    Last edited: Oct 23, 2024
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  9. Hutan

    Hutan Moderator Staff Member

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    I think the heat maps with their clustering of participants are interesting.

    Fig 1: Long covid versus Healthy controls
    Screen Shot 2024-10-23 at 3.42.10 pm.png

    Look how the HLA genes (in that dense horizontal band in the middle) really differentiate the long covid people from the controls (LC people mostly on the right side of the heat map, with down regulated HLA genes. But, the split between LC and healthy controls is messy, there are quite a few LC in clusters with healthy people on the right hand side of the diagram.

    Within the predominately Long Covid side, there are two main clusters. In one the IGHG genes are upregulated; in the other they are downreglated.


    Fig 2: ME/CFS versus healthy controls
    Screen Shot 2024-10-23 at 3.51.28 pm.png
    In the ME/CFS heat map, the ME/CFS people are mostly on the left and they are more cleanly separated from the healthy control. There are also two main ME/CFS clusters. In one, the IGHG genes are down regulated, in the other, the IGHG genes are normal-ish.

    In Figure 3, they compare the ME/CFS and LC groups, but just show the mean up or down regulation. I think that's a shame, it would have been good to see the results for each participant. With averaged results, there's not a lot of commonality between the groups, apart from the down-regulated IGHG genes.

    I wonder about the HLA results in LC. It is such a clear finding and not replicated in the ME/CFS group. Could there have been a lab error of some sort, I wonder?
     
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  10. forestglip

    forestglip Senior Member (Voting Rights)

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    I wonder how much duration of illness has to do with differences between groups. Maybe HLA is much more pronounced in the early stages, and I assume LC had shorter durations here than ME/CFS, though I don't think they report that data.
     
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  11. DMissa

    DMissa Senior Member (Voting Rights)

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    probably time since infection/onset being much shorter in LC than ME? (I havent seen their cohort data or if they include duration of illness tho)

    These necessarily rise post infection and wane gradually even in “normal” cases. If more pronounced in LC could be a feature of more severe infection than in recovered covid patients or could reflect pathology, don’t know the direction yet. Could be both at the same time

    musing from my phone but seems likely and intuitive

    edit: poster before me said the same thing. Haha
     
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  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    There seems to be the usual confusion here between genetic studies of HLA-DQ (which alleles you were born with) and gene expression studies in active cells - which are completely different issues. HLA-DQ is present on antigen presenting cells as just part of their make up. I cannot see any reason why shifts in expression rates as measured by mRNA should tell us anything at all. It is more likely to be telling us how old the cells are or some other irrelevance.

    The abstract is nonsense as usual.

    It is very disappointing that immunology isn't done at a basic level of competence.
     
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  13. Dolphin

    Dolphin Senior Member (Voting Rights)

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    Last edited: Oct 24, 2024
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