Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, complex, and long-term illness characterized by persistent fatigue and a range of physical, cognitive, and neurological issues. Mitochondrial dysfunction is strongly associated with muscle abnormalities and exercise intolerance and is widely considered one of the central mechanisms underlying ME/CFS. Previous studies have shown that serum-derived unknown factors from ME/CFS patients can induce mitochondrial alterations in healthy cells. This study was developed on the hypothesis that autoantibodies and/or autoantibody-bound proteins circulating in the serum of ME/CFS patients contribute to mitochondrial dysfunction and thereby to disease progression. A bead-based chromatography purification system was developed to purify, characterize, quantify and store large amounts of serum-derived immunoglobulin G (IgG). Using this platform, a comprehensive and standardized biobank of purified IgGs from healthy controls, ME/CFS, post-COVID ME/CFS (PCS-CFS), and multiple sclerosis (MS) patients was established. These IgGs were used in an in vitro cell culture system to study the mitochondrial structure and cellular metabolism. ME/CFS IgGs were found to induce mitochondrial fragmentation and impair cellular energetics, supporting a direct mechanistic link between patient autoantibodies and mitochondrial dysfunction. Complementary proteomic analysis of IgG-bound immune complexes revealed significant changes in immune complexes from ME/CFS patients. Therefore, large cohorts of ME/CFS and post-COVID patients from Germany, as well as external cohorts from Sweden and the UK, were used for potential biomarker validation. Increased serum FN1 levels and depleted natural antibody production, including IgM–FN1, were common factors in both ME/CFS and post-COVID patients. Together, these results provide mechanistic insight into both ME/CFS and post-COVID ME/CFS by highlighting the autoimmune features of the disease and their impact on mitochondrial function and cellular metabolism. Moreover, this work identifies a potential biomarker for ME/CFS and provides a possible explanation for the emergence of autoimmunity, as decreased natural IgM is considered to be a source of autoimmunity.
Zheng Liu (Thu,) studied this question.