Immune Activation and Inflammation
1 Chronic Immune Activation
Evidence for ongoing immune activation in ME/CFS includes:
1.1 Activation Markers
Multiple markers of immune activation are elevated in ME/CFS. Neopterin, produced by activated macrophages, is often elevated. \(\beta_2\)-microglobulin, a marker of immune cell turnover, is frequently increased. Soluble CD25 (sIL-2R) is released by activated T cells, while soluble CD14 indicates monocyte and macrophage activation.
1.2 Consequences for Energy Metabolism
Chronic immune activation is metabolically expensive. Immune cells are highly metabolically active, and cytokines alter whole-body metabolism, creating competition for nutrients between immune and other tissues. This metabolic drain may partially explain the profound fatigue characteristic of ME/CFS.
1.3 Connection to Symptoms
Cytokines and inflammatory mediators directly cause many ME/CFS symptoms. Fatigue is induced by IL-1, IL-6, TNF-\(\alpha\), and interferons. Cognitive dysfunction results from pro-inflammatory cytokines crossing the blood-brain barrier. Pain arises from sensitization of nociceptors by inflammatory mediators, while sleep disturbance reflects cytokine effects on sleep regulation. Fever and chills result from pyrogenic cytokines.
Using UK Biobank data (\(n=1{,}455\) ME/CFS cases, \(n=131{,}303\) controls) and mediation analysis, Beentjes et al. (Beentjes et al. 2025) identified hundreds of blood-based traits significantly different between ME/CFS patients and controls, including 116 traits replicated in both female and male cohorts. The pattern indicated chronic inflammation, insulin resistance, and liver disease. Critically, mediation analysis showed ME/CFS status had a significant direct effect on 290 traits but affected only 1 of 3,237 traits via an activity-duration mediator—demonstrating that these biomarker differences are not explained by reduced physical activity. Nine of fourteen traits were independently replicated in the All-of-Us cohort, and post-exertional malaise correlated with more pronounced biomarker alterations. Study: (UK Biobank + All-of-Us replication, \(n=132{,}758\) total, EMBO Molecular Medicine 2025, certainty: 0.75).
2 Neuroinflammation
The brain was traditionally considered “immune privileged,” but it is now recognized that peripheral inflammation affects brain function.
2.1 Microglial Activation
Microglia are the brain’s resident immune cells. PET imaging shows increased TSPO binding, a marker of microglial activation, which persists years after initial infection. Activated microglia produce local cytokines that affect neuronal function, potentially explaining the cognitive symptoms prevalent in ME/CFS. Independent of this still-contested ME/CFS TSPO signal (see the limitation below), a cross-disease anchor for the relevance of sustained central glial activation is provided by a large electronic-health-record cohort: acute brain-parenchymal inflammation (encephalitis) predicts a two- to five-fold increase in long-term dementia risk, strongest for non-infectious/post-infectious inflammatory (autoimmune) etiologies (Aditi et al. 2026), and chronic CNS inflammatory conditions are mechanistically grounded in microglial/astroglial activation and NLRP3 signaling (Heneka et al. 2025) (Cohen et al. 2024) (Section encephalitis dementia precedent).
2.2 Blood-Brain Barrier Dysfunction
Compromise of the blood-brain barrier permits entry of peripheral cytokines and infiltration of immune cells into the central nervous system. This dysfunction also exposes the brain to circulating autoantibodies and, in some cases, allows direct pathogen entry.
2.3 Cytokine Effects on Brain Function
Peripheral cytokines affect the brain through multiple routes: transport across the blood-brain barrier, signaling via vagal afferents, acting at circumventricular organs (which lack a blood-brain barrier), and inducing local cytokine production by glial cells. These cytokines produce multiple brain effects, including altered neurotransmitter synthesis and release, changed receptor expression, and modified synaptic plasticity. The resulting “sickness behavior” encompasses fatigue, social withdrawal, and anhedonia—symptoms prominently featured in ME/CFS.
2.4 Neuroimaging Evidence
Studies have demonstrated:
- Increased microglial activation on PET
- Elevated CSF inflammatory markers
- Correlation between brain inflammation and symptoms
- Persistence of neuroinflammation
The single published TSPO PET study in ME/CFS (n=9 patients, n=10 controls) found no significant difference in TSPO binding between groups (Raijmakers et al. 2021), contrary to neuroinflammation hypotheses. However, this null finding may be confounded by multiple methodological limitations:
- First-generation tracer [11C]-PK11195 has poor signal-to-noise compared to modern second- and third-generation tracers (PBR28, DPA-714, LW223)
- Small sample size (n=9) provides limited statistical power
- Brain-only imaging cannot assess peripheral inflammation contribution
- BBB transport confounding: Peripheral inflammation (common in ME/CFS) reduces TSPO tracer brain influx rate (Barzon et al. 2026), potentially masking central microglial activation
The BBB transport limitation is particularly relevant for ME/CFS interpretation: Barzon et al. (2026) analyzed 358 TSPO PET scans across multiple tracers and demonstrated that peripheral inflammation (elevated CRP) correlates with reduced tracer brain influx (K1). If ME/CFS involves systemic inflammation as suggested by plasma proteomics data, normal brain TSPO binding may reflect BBB dysfunction rather than absence of neuroinflammation.
Clinical implications: Negative TSPO PET results in ME/CFS cannot be interpreted as definitive evidence against neuroinflammation without measuring BBB permeability or controlling for peripheral inflammation. Replication status: Single ME/CFS study (Raijmakers et al. 2021), not replicated. BBB transport mechanism (Barzon et al. 2026) demonstrated in depression and schizophrenia, not yet tested in ME/CFS.
3 Immune Cell Displacement from Tissue Niches
The CureME biobank study (251 ME/CFS patients, 107 controls, 46 MS patients) found that overall immune cell proportions were largely normal, with one notable exception: mucosal-associated invariant T (MAIT) cells were significantly elevated in peripheral blood, with the effect strongest in severely affected patients (CD8+ MAIT AUC 0.756 for discriminating severe ME/CFS from controls). A modest shift toward effector memory CD8+ T cells was also observed.
MAIT cells are normally tissue-resident—they belong in mucosal tissues (gut, lung, liver) where they respond to bacterially-derived riboflavin metabolites. Finding them elevated in blood may indicate displacement from their normal tissue locations.
Certainty: 0.20. Highly speculative framework connecting disparate observations. MAIT cell elevation in ME/CFS blood has not been independently replicated.
If MAIT cells have been displaced from mucosal tissues into the blood, other tissue-resident immune cell populations may also be dislocated. Post-infectious tissue damage (gut epithelial disruption, blood-brain barrier compromise) could dislodge immune cells from their functional niches. In this model:
- MAIT cells appear in blood because gut mucosal architecture is disrupted (consistent with the gut microbiome abnormalities documented in Chapter Gastrointestinal and Microbiome Dysfunction)
- NK cells are functionally impaired because they are not receiving tissue-derived signals (cytokines, direct cell contacts) that exist in their normal microenvironments—their dysfunction is contextual, not cell-intrinsic
- Blood-based studies consistently miss the pathology because they sample cells that are in transit or displaced, not cells performing their actual function in tissues
This framework provides an alternative explanation for the Paradox of Invisible Immunity (Section The Paradox of Invisible Immunity): blood looks “normal” because the cells in blood are normal—they are simply not the ones doing the work. The pathology is in the tissues, where immune niches have been disrupted and resident cells are absent.
Testable predictions: (a) Tissue biopsies (gut mucosa, muscle) from ME/CFS patients should show depleted tissue-resident immune populations corresponding to the cell types found elevated in blood; (b) MAIT cell tissue frequency should inversely correlate with blood MAIT frequency within individual patients; (c) interventions that restore mucosal integrity (e.g., gut barrier repair) should normalize MAIT cell distribution.
Falsification: MAIT cell elevation is not replicated, or tissue biopsies show normal resident immune populations despite elevated blood MAIT cells.