Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise

“…In the CNS, B2M can also negatively affect hippocampal neurogenesis and synaptic plasticity and has been linked to clinical depression (Lamers et al., 2016 ). While B2M dysregulation has not been previously identified in ME/CFS patients, this finding is consistent with dysfunctional adaptive immune cells in ME/CFS (Maya, 2023 ).…”

Case report: Rapid improvements of anorexia nervosa and probable myalgic encephalomyelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes

“…The microbiome may represent a potential link; microbiota affect the immune system (31), disrupt gut-brain communication, and may trigger eating disorders including AN (32). Disrupted T cell tolerance and autoantibodies were observed in AN (31) and there is also evidence for immuno-metabolic dysfunction in T cell and natural killer (NK) cell populations in ME/CFS (33). Speculatively, alterations of the immune response and the production of autoantibodies might be a common pathogenic substrate for both conditions.…”