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

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]

 

HLA-DQA1 and HLA-DQB1 have been highlighted previously, eg —

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing (2024, Journal of Translational Medicine)

‭Multi-ancestry GWAS of Long COVID identifies‬ ‭immune-related loci and etiological links to chronic fatigue‬ syndrome, fibromyalgia and depression‬ ‭ (2024, Preprint: MedRxiv)

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome (2023, Nature Scientific Reports)

Fine mapping of the major histocompatibility complex MHC in myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS suggests involvement of both HLA class I and class II loci (2021, Brain, Behavior, and Immunity)

Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS (2020, Nature Scientific Reports)

Even DNA methylation signatures of functional somatic syndromes: Systematic review (2023, Psychosomatic Medicine)

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S4ME search links: HLA-DQA1, HLA-DQB1

 

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.

 

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

 

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."

 

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

Some other interesting bits:

 

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.

 

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.

 

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

 

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.

 

Press release:
Immune exhaustion at the core of new ME/CFS and Long COVID research
https://news.griffith.edu.au/2024/1...e-core-of-new-me-cfs-and-long-covid-research/