Oxidative and Nitrosative Stress and Immune-inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.

Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities

“…In addition, higher peripheral levels of IL-1, IL-6, and TNF-α are also observed in CFS patients compared to healthy controls [20,98] . Finally, CFS (like depression) is accompanied by mitochondrial dysfunction [99] and increased O&NS [100,101] , which play a key role in CFS.…”

“…Furthermore, changes in microbiota composition have been noted in CFS; for instance, levels of Dialister appear to be decreased in CFS [104] , similarly to findings observed in samples with MDD [11] , whereas levels of Alistipes are increased in both diseases, though less consistently so in MDD [11,45,105] . It is noteworthy that CFS frequently co-occurs with IBS, and gut inflammation and endotoxemia may play a patho-etiological role in both diseases [100,106,107] . Similarly to MDD, CFS is characterized by a propensity towards O&NS-induced autoimmune responses [108] .…”

“…Furthermore, CFS is accompanied by inducible NO synthase activation and peripheral markers of O&NS like thiobarbituric acid reactive substances (indicative of lipid peroxidation) and oxidized LDL [100,109] . As in MDD, antioxidant levels are diminished in CFS, including zinc and dehydroepiendrosterone sulphate [110,111] .…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Mechanisms underpinning the detrimental effects of excessive ROS levels on synaptic function are underpinned by oxidation of cytosolic and membrane proteins and peroxidation of membrane lipids [243,244]. For example, several research teams have reported that lipid peroxidation in presynaptic membranes impedes fusion pore opening, thereby restricting SV exocytosis, resulting in the abnormal retention of SVs within presynaptic active zones [245,246].…”

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

“…The formation of protein carbonyls via the reaction between reactive aldehydes and ketones can function as damage-associated molecular patterns (DAMPS) activating Toll-like receptors (TLRs) in turn activating nuclear factor (NF)-κB and up-regulating the production of proinflammatory cytokines and a plethora of other inflammatory molecules [14,15]. The corruptive effects of unbalanced or excess radical species also lead to adverse changes in macromolecule function and an altered conformation which occasionally renders them immunogenic and an additional source of O&NS and chronic inflammation [16,17]. These and other mechanisms explain why chronic O&NS and chronic inflammation co-exist and self-amplify in a vicious self-sustaining spiral [6,18].…”