Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Morris, Gerwyn; Maes, Michaël

doi:10.1016/j.mehy.2012.07.034

Cited by 52 publications

(49 citation statements)

References 127 publications

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“…[127]). Recent evidence has challenged the view that patients with ME/CFS display an activated Th2 dominated immune system [5,128]. Proinflammatory and anti-inflammatory cytokines are known to coexist also in ME/CFS, although in many patients proinflammatory cytokines are dominant [127,129,130].…”

Section: Discussionmentioning

confidence: 99%

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Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Morris

Maes

2013

BMC Med

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136

144

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Background‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.DiscussionThere are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.SummaryThis review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.

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Section: Discussionmentioning

confidence: 99%

“…Increased levels of proinflammatory cytokines are likely involved in the development and maintenance of fatigue in MS [319]. Raised levels of O+NS and mitochondrial dysfunctions could also conspire together to cause fatigue and the post-exertional malaise experienced by people with MS [8,128]. …”

Section: Discussionmentioning

confidence: 99%

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Morris

Maes

2013

BMC Med

Self Cite

136

144

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“…This evidence is consistent with the notion that inflammatory markers may also play a role in the pathophysiology of CFS and FM (Pariante, 2009). Levels of pro-inflammatory cytokines, such as IL-1, tumour necrosis factor (TNF)-α ) and nuclear factor (NF)-κB (Morris & Maes, 2012), have been shown to be higher in CFS patients than in healthy controls. In addition, Raison et al (2009) demonstrated that CRP levels are significantly higher in subjects with CFS and insufficient fatigue (ISF, a milder form of chronic fatigue) when compared with healthy control subjects.…”

Section: Discussionmentioning

confidence: 99%

Childhood stressors in the development of fatigue syndromes: a review of the past 20 years of research

et al. 2013

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“…Such reduction of IKKβ function leads to attenuated proteasomal degradation of IkB because of reduced ubiquitination, ultimately providing another mechanism resulting in NF-kβ inhibition [35,124,125]. Given that NFkβ is activated in response to excessive O&NS [126] and is a master regulator of the immune response [9], S-nitrosylation may modulate the immune response.…”

Section: Hypernitrosylation and Pathologymentioning

confidence: 99%

“…However, it is only recently recognized that the major regulatory role exerted by NO on multiple aspects of cellular function and redox signaling [4,5] is strongly mediated by S-nitrosylation (SNO) [6][7][8]. Despite being a relatively stable free radical, NO is prone to decomposition and reacts readily with other molecules to form an array of radical or nonradical entities collectively described as reactive nitrogen species (RNS) [9]. These compounds in turn can react with a range of protein residues modifying the structure and function of the proteins involved [10].…”

Section: Introductionmentioning

confidence: 99%

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Morris¹,

Berk

Klein

et al. 2016

Mol Neurobiol

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Nitric oxide plays an indispensable role in modulating cellular signaling and redox pathways. This role is mainly effected by the readily reversible nitrosylation of selective protein cysteine thiols. The reversibility and sophistication of this signaling system is enabled and regulated by a number of enzymes which form part of the thioredoxin, glutathione, and pyridoxine antioxidant systems. Increases in nitric oxide levels initially lead to a defensive increase in the number of nitrosylated proteins in an effort to preserve their function. However, in an environment of chronic oxidative and nitrosative stress (O&NS), nitrosylation of crucial cysteine groups within key enzymes of the thioredoxin, glutathione, and pyridoxine systems leads to their inactivation thereby disabling denitrosylation and transnitrosylation and subsequently a state described as "hypernitrosylation." This state leads to the development of pathology in multiple domains such as the inhibition of enzymes of the electron transport chain, decreased mitochondrial function, and altered conformation of proteins and amino acids leading to loss of immune tolerance and development of autoimmunity. Hypernitrosylation also leads to altered function or inactivation of proteins involved in the regulation of apoptosis, autophagy, proteomic degradation, transcription factor activity, immune-inflammatory pathways, energy production, and neural function and survival. Hypernitrosylation, as a consequence of chronically elevated O&NS and activated immune-inflammatory pathways, can explain many characteristic abnormalities observed in neuroprogressive disease including major depression and chronic fatigue syndrome/myalgic encephalomyelitis. In those disorders, increased bacterial translocation may drive hypernitrosylation and autoimmune responses against nitrosylated proteins.

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Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Cited by 52 publications

References 127 publications

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Childhood stressors in the development of fatigue syndromes: a review of the past 20 years of research

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

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