Monday, 24 August 2015

Does the immune system cause autonomic dysfunction in ME/CFS?

Autonomic dysfunction (dysautonomia) is a major feature of ME/CFS 1–4. The autonomic nervous system regulates many things of relevance (e.g. blood flow, heart rate, immune function and energy metabolism) 5, so could contribute to multi-system dysfunction.

Autonomic dysfunction in ME/CFS seems to involve both sympathetic (fight/flight) and parasympathetic (rest/digest) responses. For instance at baseline there can be an increased heart rate, lower heart rate variability (HRV) during sleep 1,4, and a prolonged acetylcholine-induced peripheral vasodilation 6. Challenging autonomic function with tilt tests reveal an increased heart rate, frequency of POTS and neural-mediated hypotension 1. Autonomic dysfunction has been linked to muscle pH handling 3, which has itself been linked to cerebrovascular control 2. There will also likely be relationships with impaired cardiac function (and low blood pool volume) 7, GI dysfunction 8 and perhaps postprandial somnolence (food coma) in some people with ME/CFS.

So autonomic dysfunction could be a central feature of ME/CFS, driving much systemic dysfunction 2,3. But what causes autonomic dysfunction? I’ve been surprised by how little interest and research there has been regarding potential causes. Of several possibilities, an immune-mediated mechanism seems plausible, as discussed below.

ME/CFS typically occurs after infections, which likely trigger pathogenesis, and somehow autonomic dysfunction. Most obvious would be inflammatory cytokines acting on neurological tissue to mediate adaptive responses to infection (i.e. sickness behaviour). However sickness behaviour doesn’t seem to have a particularly clear set of autonomic changes resembling those in ME/CFS, which itself involves far more complex changes beyond those seen in sickness behaviour 9. This may be because the autonomic changes following infection have not been well-studied (e.g. how does facial pallor/paleness occur?). Anyway, another possibility would be that chronic immune activation in ME/CFS has induced further sequelae (e.g. metabolic dysfunction) which mediates the autonomic dysfunction 9; for instance autonomic dysfunction is common in mitochondrial diseases 10.

Chronic immune activation could be driven by on-going infection in the nervous system, as proposed by 2 hypotheses in ME/CFS (i.e. peripheral ganglia 11 and vagus nerve 12). Certainly chronic infections are frequently found in CNS tissue in other chronic illnesses (e.g. MS) 13. Another possibility is on-going infection in the gut. Several GI infections (i.e. enterovirus, parvovirus B19 and HERVs) and mild mucosal inflammation have been reported in ME/CFS 14–16. This might stimulate enteric/vagal activity. For instance gastroenteritis commonly leads to activation of the vagus nerve and increased parasympathetic activity. In fact excessive vagal stimulation can induce the vasovagal response and even syncope (fainting). Altered vagal tone occurs in chronic gut conditions including IBS and Crohn’s 17. Also gut dysbiosis, the vagus nerve and autonomic dysfunction are emerging players in the aetiology of Parkinson’s disease 18–20.

A further possibility is that a pathogenic autoimmune response might be causing autonomic dysfunction in ME/CFS. Certainly many autoimmune responses have been reported in ME/CFS, most to intracellular molecules and neurological receptors 21, although it’s not clear which ones are pathogenic. The potential importance of autoimmunity is emphasised by preliminary studies with Rituximab, which depletes B cells and achieves significant improvements in ~60% of ME/CFS patients 22,23. This led the authors to suggest pathogenic B cell-derived autoantibodies may be at play. They further suggested autoimmune-induced autonomic dysfunction as a possible candidate mechanism, based on new findings in related conditions 23. For instance agonistic (activating) autoantibodies to autonomic receptors have been found in POTS 24 and orthostatic hypotension 25,26, both of which occur in subsets of ME/CFS. Autoimmune responses to autonomic receptors have actually also been found in some with ME/CFS 21. Furthermore some functional significance is implied by a correlation between blood autoantibody responses to mAChR and decreased receptor binding in the brain in CFS, although there was no correlation with cognitive symptoms 27.

Autoimmune responses could result from many things, perhaps the most obvious being infections, leaky gut and cell damage in ME/CFS 21. Interestingly there is at least one case study of influenza A-induced autoimmunity resulting in orthostatic hypotension, which was rapidly and completely reversed by IV immunoglobulin G (IVIG) treatment 28. Note IVIG has also been used to successfully treat CFS resulting from parvovirus 29.

References
1.         Van Cauwenbergh, D. et al. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review. Eur. J. Clin. Invest. 44, 516–26 (2014).
2.         He, J., Hollingsworth, K. G., Newton, J. L. & Blamire, A. M. Cerebral vascular control is associated with skeletal muscle ph in chronic fatigue syndrome patients both at rest and during dynamic stimulation. NeuroImage Clin. 2, 168–173 (2013).
3.         Jones, D. E. J., Hollingsworth, K. G., Taylor, R., Blamire, a M. & Newton, J. L. Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. J. Intern. Med. 267, 394–401 (2010).
4.         Meeus, M. et al. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review. Semin. Arthritis Rheum. 43, 279–87 (2013).
5.         Mathias, C. J. Autonomic diseases: clinical features and laboratory evaluation. J. Neurol. Neurosurg. Psychiatry 74 Suppl 3, iii31–i41 (2003).
6.         Khan, F., Spence, V., Kennedy, G. & Belch, J. J. F. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin. Physiol. Funct. Imaging 23, 282–5 (2003).
7.         Hollingsworth, K. G., Hodgson, T., Macgowan, G. A., Blamire, A. M. & Newton, J. L. Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. J. Intern. Med. 271, 264–70 (2012).
8.         Sperber, A. D. & Dekel, R. Irritable Bowel Syndrome and Co-morbid Gastrointestinal and Extra-gastrointestinal Functional Syndromes. J. Neurogastroenterol. Motil. 16, 113–9 (2010).
9.         Morris, G., Anderson, G., Galecki, P., Berk, M. & Maes, M. A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med. 11, 64 (2013).
10.       Morris, G. & Maes, M. Mitochondrial dysfunctions in Myalgic Encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab. Brain Dis. 29, 19–36 (2014).
11.       Shapiro, J. S. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med. Hypotheses 73, 728–34 (2009).
12.       VanElzakker, M. B. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med. Hypotheses 81, 414–23 (2013).
13.       Nicolson, G., Settineri, R. & Ellithorpe, R. Neurodegenerative and Fatiguing Illnesses, Infections and Mitochondrial Dysfunction: Use of Natural Supplements to Improve Mitochondrial Function. Funct. Foods Heal. Dis. 4, 23–65 (2014).
14.       DE Meirleir, K. L. et al. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo 27, 177–87 (2013).
15.       Chia, J. K. S. & Chia, A. Y. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J. Clin. Pathol. 61, 43–8 (2008).
16.       Frémont, M., Metzger, K., Rady, H., Hulstaert, J. & De Meirleir, K. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo 23, 209–13 (2009).
17.       Pellissier, S. et al. Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn’s disease and irritable bowel syndrome. PLoS One 9, e105328 (2014).
18.       Kelly, L. P. et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov. Disord. 29, 999–1009 (2014).
19.       Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6, e28032 (2011).
20.       Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. (2014). doi:10.1007/s00401-014-1343-6
21.       Morris, G., Berk, M., Galecki, P. & Maes, M. The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol. Neurobiol. 49, 741–56 (2014).
22.       Fluge, O. et al. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS One 6, e26358 (2011).
23.       Fluge, Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One 10, e0129898 (2015).
24.       Li, H. et al. Autoimmune basis for postural tachycardia syndrome. J. Am. Heart Assoc. 3, e000755 (2014).
25.       Yu, X. et al. Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an ‘autoimmune’ orthostatic hypotension. J. Am. Soc. Hypertens. 6, 40–7 (2012).
26.       Li, H. et al. Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Hypertension 59, 402–8 (2012).
27.       Yamamoto, S. et al. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One 7, e51515 (2012).
28.       Lukkarinen, H. & Peltola, V. Influenza A induced acute autonomic neuropathy in an adolescent. Pediatr. Neurol. 43, 425–6 (2010).
29.       Kerr, J. R. & Tyrrell, D. A. J. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr. Pain Headache Rep. 7, 333–41 (2003).


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