Liu et al. (2025)
- Authors: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Stephanie Lamer, Andreas Schlosser, Emils Edgars Basens, Georgy Nikolayshvili, Liba Sokolovska, Gabriela Riemekasten, Rebekka Rust, Judith Bellmann-Strobel, Friedemann Paul, Robert K. Naviaux, Zaiga Nora-Krukle, Franziska Sotzny, Carmen Scheibenbogen, Bhupesh K. Prusty
- Institutes: Institute of Virology and Immunobiology, University of WĂŒrzburg, Germany; Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, CA, USA; Rudolf Virchow Center, Center for Translational Bioimaging, Julius-Maximilians-University of WĂŒrzburg, Germany; Institute of Microbiology and Virology, Riga StradiĆĆĄ University Research Center, Riga, Latvia; Klinik fĂŒr Rheumatologie, UniversitĂ€tsklinikum Schleswig-Holstein, LĂŒbeck; Experimental and Research Center (ECRC), CharitĂ© - UniversitĂ€tsmedizin Berlin, Corporate Member of Freie UniversitĂ€t Berlin, Humboldt UniversitĂ€t zu Berlin and Berlin Institute of Health, Berlin, Germany; NeuroCure Research Centre, CharitĂ© UniversitĂ€tsmedizin Berlin, Corporate Member of Freie UniversitĂ€t Berlin, Humboldt UniversitĂ€t zu Berlin and Berlin Institute of Health, Berlin, Germany; Departments of Medicine, Pediatrics, and Pathology, University of California, San Diego School of Medicine, San Diego, USA; Institute of Medical Immunology, CharitĂ© UniversitĂ€tsmedizin Berlin, Corporate Member of Freie UniversitĂ€t Berlin and Humboldt UniversitĂ€t zu Berlin and Berlin Institute of Health, Berlin, Germany.
- Publisher: medRxiv
- Link: DOI
Summary
This study provides direct laboratory evidence that antibodies (IgG) from ME/CFS patients can damage the mitochondriaâthe energy factoriesâof healthy cells. This reinforces the theory that ME/CFS is an autoimmune disease and offers a potential biological explanation for the profound energy impairment experienced by patients. The research also uncovered key differences between ME/CFS and Long COVID (PASC) at a molecular level; ME/CFS appears linked to issues with the structural support around cells (extracellular matrix), while PASC is more associated with blood clotting pathways. These findings could pave the way for developing more specific diagnostic tests and treatments aimed at correcting these antibody-driven problems.
What was researched?
This study investigated whether immunoglobulins (specifically IgG antibodies) isolated from the blood of ME/CFS and PASC (Long COVID) patients could directly cause mitochondrial dysfunction in healthy human cells. The researchers examined the effects of these patient-derived IgGs on mitochondrial structure, cellular energy production, and the secretion of inflammatory markers, and also analyzed the composition of proteins bound to the IgGs.
Why was it researched?
Mitochondrial dysfunction and immune system abnormalities are known features of ME/CFS, but the direct cause linking them is not fully understood. Previous research suggested an autoimmune component, as transferring IgG from patients to mice could induce symptoms. This study aimed to test the hypothesis in vitro (in a lab dish) that IgG from patients is a direct driver of the mitochondrial and metabolic problems seen in the disease.
How was it researched?
This was an in vitro laboratory study using purified IgG antibodies from the blood serum of ME/CFS patients (n=40), PASC patients (n=16), multiple sclerosis patients (n=11), and healthy controls (n=39). The researchers exposed healthy human endothelial cells (HUVECs) to these IgGs and used microscopy to observe changes in mitochondrial structure. They measured cellular energy metabolism using a Seahorse Extracellular Flux Analyzer and also exposed healthy immune cells (PBMCs) to the IgGs to measure inflammatory cytokine release. Finally, they used mass spectrometry to identify the proteins that were bound to the patient IgGs, a technique called immune complex proteomics.
What has been found?
IgG from a subgroup of ME/CFS and PASC patients caused significant fragmentation of mitochondria in healthy endothelial cells, an effect that was more pronounced with IgG from female patients. While intact IgG was required for fragmentation, its separated âFabâ fragment alone could alter cellular energy production by increasing maximal respiration, indicating cellular stress. In contrast, the âFcâ fragment induced a hypometabolic state. Proteomic analysis revealed that ME/CFS immune complexes were enriched with proteins related to extracellular matrix organization, whereas PASC immune complexes were linked to hemostasis (blood clotting regulation).
Discussion
The authors note the complexity of the findings, where different parts of the IgG molecule (Fab vs. Fc) have distinct effects on cellular energy, and the intact molecule is needed to cause mitochondrial fragmentation. They discuss that the entry of IgG into endothelial cells is a key step, likely mediated by Fc receptors and other non-specific pathways, which could be a pathogenic mechanism in ME/CFS. The distinct protein signatures found in the immune complexes of ME/CFS versus PASC suggest that while the conditions may share symptoms, they may be driven by different underlying biological processes.
Conclusion & Future Work
The study concludes that IgG from ME/CFS and PASC patients can directly cause mitochondrial fragmentation and metabolic dysregulation in healthy cells, providing a potential pathogenic mechanism for these diseases. The differing protein compositions of immune complexes in ME/CFS and PASC may serve as disease-specific biomarkers. The authors suggest these findings support targeting antibody-mediated pathology as a potential therapeutic strategy for post-infectious illnesses.