Someone in a PM introduced me to a new study on ME

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ME/CFS was already on my disease list before Covid happened and I immediately saw the correlation when Long Covid emerged.

Did a fairly quick look at the study or as quick as I could with such a lengthy paper. ME/CFS definitely shows a pro-inflammatory signature.

Of note -

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These data are consistent with expansion of naïve B-cells by the STAT4-TLR9 and other B-cell pathways observed in PI-ME/CFS by flow cytometry.

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CCR5 increases STAT4 and in a feedback loop STAT4 increases CCR5.

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Differences in the alpha diversity of stool samples... Beta diversity, as measured by Bray–Curtis dissimilarity demonstrated significant differences in microbial community composition between the groups

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Inflammation will kill off entire colonies of specific gut bacteria decreasing biodiversity. One of the hallmarks of Crohn's disease.

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Thus, the fatigue of PI-ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored.

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I wonder if they looked at NF-H (neurofilament heavy) levels. One of the building blocks of neuronal develpment. Downregulated by inflammation, upregulated by CCR5 blockade.

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We investigated several additional biological functions in PI-ME/CFS. Previous studies have implicated abnormalities in immunity, mitochondrial function, reduction-oxidation regulation, or altered microbiome structure in this condition... PD-1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of PI-ME/CFS participants. Although NK cell function was not different between groups in blood, they showed decreased expression of a cytolytic function marker in the spinal fluid. Previous studies suggest that NK cell function is decreased in ME/CFS.

PBMC gene expression profiling showed perturbations in the T-cell activation, proteasome and NF-kB pathways. Analyses of serum and cerebrospinal fluid proteins identified several molecules related to innate immunity suggesting a distinct expression pattern in male cohorts. In contrast, in the female cohorts, gene expression profiling of PBMCs identified perturbations in B-cell and leukocyte proliferation processes with a corresponding identification of plasma lymphotoxin α1β2, which may act as a proliferative signal in secondary lymphoid tissues. Additionally, elevated levels of plasminogen in serum and eosinophil protein galactin-10, the C-C motif chemokine (MDC), and the IL 18 receptor accessory protein were present in cerebrospinal fluid of female PI-ME/CFS participants. Plasminogen and lymphotoxin α1β2 are known to activate proinflammatory states via NF-kB

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Abnormal immunity, mitochondrial dysfunction, altered microbiome, T-cell exhaustion, decreased NK cells (natural killer T-cells), IL-18, NF-kB all within the ability of leronlimab to reverse.

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The finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigen. Immune dysfunction leads to neurochemical alterations that impact neuronal circuits, which may be another point of intervention.

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https://www.nature.com/articles/s41467-024-45107-3

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