Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

BMC Medicine, Feb 2015

Background The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome. Discussion Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation. Summary It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.

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Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

Gerwyn Morris Michael Berk 0 1 Ken Walder Michael Maes 1 0 Department of Psychiatry and The Florey Institute of Neuroscience and Mental Health , Orygen , The National Centre of Excellence in Youth Mental Health, The University of Melbourne , Parkville , Australia 1 IMPACT Strategic Research Centre, School of Medicine, Deakin University , Geelong , Australia Background: The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome. Discussion: Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson's disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation. Summary: It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome. - Background There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders [1,2]. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways [3-5]. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes [1,6] activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation [7,8]. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion [1,9,10]. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue. The existence of chronically activated immune and inflammatory pathways in the periphery and their causative role in the genesis of neuroinflammation has been established in a range of neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimers and Parkinsons disease [11-16]. Many individuals with neuroinflammatory and neurodegenerative diseases also suffer from fatigue. For example, upwards of 80% of multiple sclerosis patients suffer from fatigue [17]. A study by Beiske and Svensson reported that between 37% and 57% of patients with Parkinsons disease also experience incapacitating fatigue [18]. Fatigue is one of the characteristics of major depression [19,20]. Chronic systemic inflammation and the presence of activated microglia are also found in patients with major depression [19-22]. Chronic systemic inflammation and immune activation is also an invariant finding in many patients diagnosed with chronic fatigue syndrome (CFS) even without evidence of increased pathogen load [17]. Severe chronic fatigue is also experi (...truncated)


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Gerwyn Morris, Michael Berk, Ken Walder, Michael Maes. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses, BMC Medicine, 2015, pp. 28, 13, DOI: 10.1186/s12916-014-0259-2