Autonomic dysfunction in ME/CFS: a role for the immune system?

Autonomic dysfunction (dysautonomia) is a major feature of ME/CFS ^1–4. The autonomic nervous system regulates many organs and 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 often occurs after infections, which presumably 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 achieved 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

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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).

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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).

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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).

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