E3 PreliminaryPreliminaryPEM requiredReview-NarrativePeer-reviewedReviewed
Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review.
Humer, Bart, Dik, Willem A, Versnel, Marjan A · Frontiers in immunology · 2025 · DOI
Quick Summary
This review explores how a single severe infection might trigger long-term changes in the immune system that could lead to ME/CFS. After infection, immune cells can become 'trained' to overreact to future triggers, potentially causing the chronic symptoms patients experience. The researchers suggest this overactive immune response might explain why about 60% of ME/CFS patients remember getting sick before their symptoms started.
Why It Matters
Understanding whether trained immunity contributes to ME/CFS pathogenesis could explain why infections precede symptom onset in many patients and why symptoms persist despite pathogen clearance. This mechanism might guide future diagnostic and therapeutic strategies targeting immune cell reprogramming rather than active infection.
Observed Findings
- Approximately 60% of ME/CFS patients report acute infection preceding symptom onset
- Trained immunity involves long-term epigenetic reprogramming affecting chromatin accessibility and metabolic shifts in innate immune cells
- Hematopoietic stem cells in bone marrow are necessary for long-term persistence of trained immunity
- Post-infectious diseases with ME/CFS-like symptoms also show evidence of chronic immune activation
- Trained immunity initially characterized in peripheral monocytes/macrophages but now recognized in bone marrow progenitor cells
Inferred Conclusions
- Pronounced hyperresponsiveness of innate immune cells due to trained immunity may account for aberrant activation of immune pathways in ME/CFS
- The post-infectious onset pattern in a large subset of ME/CFS cases is consistent with trained immunity-induced pathophysiology
- Trained immunity represents a plausible biological mechanism linking acute infection to chronic disease symptoms
Remaining Questions
- Is trained immunity actually present and activated in ME/CFS patients compared to healthy controls, and at what frequency?
- Which specific infections most commonly trigger trained immunity leading to ME/CFS development?
What This Study Does Not Prove
This review does not establish that trained immunity causes ME/CFS—it presents a hypothesis supported by indirect evidence from other post-infectious diseases. The review cannot prove causation, cannot quantify how frequently trained immunity occurs in ME/CFS patients specifically, and does not report novel experimental validation in ME/CFS populations. Trained immunity may be one factor among multiple contributing mechanisms.
Tags
Symptom:Post-Exertional MalaiseCognitive DysfunctionUnrefreshing SleepFatigue
Biomarker:CytokinesGene ExpressionBlood Biomarker
Phenotype:Infection-Triggered
Method Flag:Weak Case DefinitionExploratory Only
Metadata
- DOI
- 10.3389/fimmu.2025.1483764
- PMID
- 40201181
- Review status
- Editor reviewed
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 12 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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