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.