Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.

Observed Findings

• Increased frequency of total T cells paired with significant reduction in natural killer cells, monocytes, and dendritic cell subsets in ME/CFS patients.
• CD4+ and CD8+ T cells show altered differentiation states and abnormal developmental trajectories, suggesting suppressed differentiation.
• NK cells in ME/CFS patients exhibit reduced cytotoxicity markers (perforin and CD107a) with impaired functional responses.
• Memory B cells show early differentiation and increased conversion to plasma cells, indicating B cell overactivity.
• ESRRA-APP-CD74 signaling pathway identified as a potential biomarker, with higher ESRRA expression confirmed in monocytes from male ME/CFS patients in independent database.

Inferred Conclusions

• ME/CFS involves a spectrum of immune dysfunction combining autoimmune-like overactivity (B cell hyperactivation) with immunodeficiency features (reduced NK function).
• Abnormal immune cell communication networks centered on monocytes contribute to disease pathophysiology.
• Immunoneurological links may involve amyloidotic neurodegenerative signaling pathways implicated in the ESRRA pathway.
• The ESRRA-APP-CD74 pathway warrants further investigation as a diagnostic biomarker and potential therapeutic target.

Remaining Questions