Metabolic Brain Disease

, Volume 28, Issue 4, pp 523–540 | Cite as

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome

  • Gerwyn Morris
  • Michael MaesEmail author
Review Article


This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.


Chronic fatigue syndrome Inflammation Cytokines Depression Tryptophan Oxidative and nitrosative stress Mitochondria Autoimmune 



Myalgic Encephalomyelitis


World Health Organization


Chronic fatigue syndrome


Pro-inflammatory cytokines


Tumor necrosis factor




Natural killer


Oxidative and nitrosative stress


Nuclear factor κB




2-5A-dependent ribonuclease L


Protein kinase R


Cyclo-oxygenase 2


Interferon γ


T helper


Transforming growth factor


T regulatory


Adenosine triphosphate




Toll-like receptor


Blood brain barrier


Single-photon emission computed tomography


Positron emission tomography


Tesla magnetic-resonance imaging




Multiple sclerosis




Tryptophan catabolite




Nicotinamide adenine dinucleotide phosphate


Signal Transducer and Activator of Transcription 3


Forkhead box P3


Peripheral blood mononuclear cells


Single nucleotide polymorphisms



The authors would like to thank Victoria Storey and Jane Clout for secretarial services. There was no specific financial support for this study. The authors declare that they do not have a conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Tir Na NogLlanelliUK
  2. 2.Maes Clinics @ TRIABangkokThailand
  3. 3.Piyavate HospitalBangkokThailand

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