Family 4: Immune Activation and Cytokine Signalling
Family overview. The immune system coordinates defence through pattern recognition, cell-mediated killing, and soluble mediators. Chronic, non-resolving immune activation — rather than acute protective inflammation — is a shared substrate of most major chronic diseases.
Concrete mechanisms and ME/CFS evidence:
Innate immune hyperactivation. Multi-omics analysis identifies exaggerated innate immune response as a primary driver of chronic inflammation and PEM; heightened TLR signalling and pattern recognition receptor activation (Cheng et al. 2025).
NK cell cytotoxic exhaustion. Meta-analysis confirms NK cytotoxicity at roughly half healthy control levels; elevated inhibitory KIR alleles (KIR3DL3*002) suppress killing signals; reduced perforin and granzyme delivery.
T cell immunosenescence and exhaustion. CD4⁺ and CD8⁺ T cells show epigenetic predisposition toward terminal exhaustion; reduced proliferative capacity; dysregulated transcriptome at single-cell resolution. Regulatory NK cells elevated; γδ T cells proportionally increased.
Pro-inflammatory cytokine excess. Elevated IL-1β, IL-6, TNF-α, and IL-8; Hornig et al. identified a disease-duration-dependent cytokine signature (Hornig et al. 2015) — early-phase ME/CFS shows different cytokine profile from long-duration disease, suggesting temporal evolution of immune dysregulation.
Type I interferon dysregulation. Altered IFN-α/β signalling; elevated interferon scores in some cohorts, consistent with ongoing viral sensing or nucleic acid danger signals.
Complement system activation. Complement dysregulation documented in ME/CFS and Long COVID; C5a and C5b-9 membrane attack complex contribute to endothelial damage, mitochondrial stress, and microvascular dysfunction (Cervia-Hasler et al. 2024).
Mast cell activation. Up to 25% of ME/CFS patients meet criteria for clinically relevant mast cell activation (MCAS); mast cell mediators (histamine, tryptase, prostaglandins) cause vasodilation, vascular leakage, connective tissue degradation, and sensory nerve sensitisation (Dinser et al. 2025).
Dendritic cell and monocyte dysfunction. Reduced conventional and plasmacytoid DCs; altered monocyte metabolic state; impaired antigen presentation capacity. Blood pDC depletion has been documented across multiple viral infections (HIV, HCV, HBV, COVID-19) and autoimmune diseases (SLE, RA), with evidence suggesting chemokine-mediated blood→tissue migration (CXCR3/CXCL9-11, CXCR4/CXCL12) rather than absolute cell loss (Van der Sluis, Holm, and Jakobsen 2022) (Li et al. 2017). If confirmed in ME/CFS, consequences would include systemic DNase1L3 deficiency (impaired NET degradation) and reduced systemic type I IFN production (Garcia et al. 2024) (Pérez-Gómez et al. 2021); however, no pDC-specific data exist in ME/CFS and these consequences remain extrapolated from other conditions.
Neutrophil dysfunction. Elevated neutrophil apoptosis; potential impairment of neutrophil extracellular trap (NET) formation and pathogen clearance. In post-viral contexts, imbalance between NET production and DNase-mediated NET degradation (NET/DNase dysregulation) may drive thrombo-inflammation and autoantigen generation across conditions (Garcia et al. 2024).
Full discussion: Immune System Dysfunction.
Evidence status: Established (most findings independently replicated; NK cytotoxicity and cytokine findings among the most robust in the field).