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

Abstract

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.

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Abbreviations

ME:

Myalgic Encephalomyelitis

WHO:

World Health Organization

CFS:

Chronic fatigue syndrome

PICs:

Pro-inflammatory cytokines

TNFα:

Tumor necrosis factor

IL-6:

Interleukin-6

NK:

Natural killer

O&NS:

Oxidative and nitrosative stress

NF-κB:

Nuclear factor κB

2-5A:

2′-5′-oligoadenylate

RNaseL:

2-5A-dependent ribonuclease L

PKR:

Protein kinase R

COX-2:

Cyclo-oxygenase 2

IFNγ:

Interferon γ

Th:

T helper

TGF-β1:

Transforming growth factor

Treg:

T regulatory

ATP:

Adenosine triphosphate

LPS:

Lipopolysaccharide

TLR:

Toll-like receptor

BBB:

Blood brain barrier

SPECT:

Single-photon emission computed tomography

PET:

Positron emission tomography

T MRI:

Tesla magnetic-resonance imaging

HPA:

Hypothalamic-pituitary-adrenal

MS:

Multiple sclerosis

IDO:

2,3-dioxygenase

TRYCAT:

Tryptophan catabolite

NMDA:

N-methyl-D-aspartate

NADP:

Nicotinamide adenine dinucleotide phosphate

STAT3:

Signal Transducer and Activator of Transcription 3

Foxp3:

Forkhead box P3

PBMCs:

Peripheral blood mononuclear cells

SNPs:

Single nucleotide polymorphisms

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Acknowledgments

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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Morris, G., Maes, M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis 28, 523–540 (2013). https://doi.org/10.1007/s11011-012-9324-8

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Keywords

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