hypothesis – Page 7 – American ME and CFS Society

Do vasoactive neuropeptides and heat shock proteins mediate fatigue-related autoimmune disorders?

Abstract:

Autoimmune dysfunction of certain vasoactive neuropeptides may be implicated in a range of disorders associated with fatigue like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome. These substances have neurotrophic, neuroregulatory, and neurotransmission functions, as well as that of immune modulators and hormones. They exert significant control over carbohydrate and lipid metabolism.

The hypothesis is that because these substances have vital and indispensable roles in cellular processes, loss or compromise of these roles would lead to predictable and severe cellular and systemic effects. The important roles of certain VNs make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. While peptide-HSP complexes are a relatively new area for research, this paper asserts that attention could be focused on these substances and complexes in an effort to elucidate a number of perplexing fatigue-associated disorders.

Source: Staines DR. Do vasoactive neuropeptides and heat shock proteins mediate fatigue-related autoimmune disorders? Med Hypotheses. 2005;64(3):539-42. http://www.ncbi.nlm.nih.gov/pubmed/15617862

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

Abstract:

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations.

First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension.

Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

Source: Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004;62(5):759-65. http://www.ncbi.nlm.nih.gov/pubmed/15082102

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

Abstract:

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory.

Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis.

This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition.

The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.

Source: Staines DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? Med Hypotheses. 2004;62(5):646-52. http://www.ncbi.nlm.nih.gov/pubmed/15082083

Dysautonomia in chronic fatigue syndrome: facts, hypotheses, implications

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is based on patient history and treatment on cognitive behavior therapy and graded exercise. There is increasing evidence that dysautonomia occurs in CFS manifest primarily as disordered regulation of cardiovascular responses to stress. We impart our experience relating to diagnosis, monitoring, and treatment of CFS based on identification and management of dysautonomia.

Recently proposed methods for assessment of the cardiovascular reactivity, the ‘hemodynamic instability score’ (HIS) and the ‘Fractal and Recurrence Analysis-based Score’ (FRAS), served for this purpose. On HUTT, a particular dysautonomia is revealed in CFS patients that differ from dysautonomia in several other disorders. This distinct abnormality in CFS can be identified by HIS >-0.98 (sensitivity 84.5% and specificity 85.1%) and FRAS > +0.22 (sensitivity 70% and specificity 88%). Therefore, the HIS and FRAS may be used, in the appropriate clinical context, to support the diagnosis of CFS, which until now, could only be subjectively inferred.

A pilot study suggested that midodrine treatment, directed at the autonomic nervous system in CFS, results first in correction of dysautonomia followed by improvement of fatigue. This finding implies that dysautonomia is pivotal in the pathophysiology CFS, at least in a large part of the patients, and that manipulating the autonomic nervous system may be effective in the treatment of CFS.

Source: Naschitz JE, Yeshurun D, Rosner I. Dysautonomia in chronic fatigue syndrome: facts, hypotheses, implications. Med Hypotheses. 2004;62(2):203-6. http://www.ncbi.nlm.nih.gov/pubmed/14962627

Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients

Abstract:

Protein carbonyl levels, a measure of protein oxidation, were found to be significantly elevated (p < 0.0005) in the sera of chronic fatigue syndrome (CFS) patients vs. controls. In contrast, the total protein levels in sera CFS patients were unchanged from those of controls. The elevated protein carbonyl levels confirm earlier reports suggesting that oxidative stress is associated with chronic fatigue syndrome and are consistent with a prediction of the elevated nitric oxide/peroxynitrite theory of chronic fatigue syndrome and related conditions.

Source: Smirnova IV, Pall ML. Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Mol Cell Biochem. 2003 Jun;248(1-2):93-5. http://www.ncbi.nlm.nih.gov/pubmed/12870659

Atypical depression as a secondary symptom in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) has gained prominence since 1988 and a substantial amount of research has been done in this domain. However, it is still regarded as a controversial condition. Moreover, most of the symptoms of CFS itself are non-specific, occurring in many illnesses; some of the symptoms are also common in depression. Indeed, an area of continued controversy and debate involves the diagnostic overlap between CFS and psychiatric disorders. Through anecdotal evidence, atypical depression appears to be common in CFS. Recent developments in psychobiology underscore the role of the acute phase response and its associated sickness behavior in affective disorders. Thus, we hypothesize that atypical depression is sickness behavior rather than an affective disorder as shown by anecdotal evidence in CFS.

Source: Van Hoof E, Cluydts R, De Meirleir K. Atypical depression as a secondary symptom in chronic fatigue syndrome. Med Hypotheses. 2003 Jul;61(1):52-5. http://www.ncbi.nlm.nih.gov/pubmed/12781640

The investigation of chronic fatigue syndrome: a case-study of the limitations of inductive inferences and non-falsifiable hypotheses in medical research

Abstract:

Karl Popper’s argument that deductive logic and falsifiable hypotheses are necessary for the growth of scientific knowledge has been controversial. One approach to assess the relevance of his ideas to medical science has been to evaluate examples of successful research. Another approach is to analyze an unsuccessful investigation. The inconclusive search for a unique ‘chronic fatigue syndrome’ offers a well-documented case-study for this analysis. Over the past 130 years, numerous studies have provided clinical and epidemiological data, which have supported competing hypotheses about the etiology of chronic fatigue. However, few hypotheses have been refuted because it has not been possible to establish objective standards of inquiry for a subjective symptom like fatigue. As a result, intensive research efforts have not converged on correct explanations by eliminating erroneous ideas. This unsuccessful investigation illustrates how non-falsifiable hypotheses are insufficient to advance medical knowledge, even when there is an abundance of empirical data.

Source: Hyams KC. The investigation of chronic fatigue syndrome: a case-study of the limitations of inductive inferences and non-falsifiable hypotheses in medical research. Med Hypotheses. 2003 May;60(5):760-6. http://www.ncbi.nlm.nih.gov/pubmed/12710915

Chronic fatigue syndrome – medical fact or artifact

Abstract:

Despite extensive investigation, the enigma of Chronic Fatigue Syndrome (CFS) continues to confound medical researchers. It is suggested that this may be due to two impediments inherent in their overall approach to the problem.

Firstly, although fatigue is central to CFS, medical scientists appear not to understand what fatigue itself really is, nor what is its purpose or mode of function. A functional definition of fatigue is suggested to help resolve this.

Secondly, physicians and other researchers – psychologists and alternative medicine practitioners – fail to observe an elementary and fundamental procedure of clinical medicine, namely, that of properly examining their patients before making a diagnosis or providing treatment. The notion of the ‘black hole’ of medicine is introduced. Recognizing the existence of these impediments is considered a self-evident precondition for further significant progress being made in this field.

Source: Eidelman D. Chronic fatigue syndrome – medical fact or artifact. Med Hypotheses. 2003 Jun;60(6):840-2. http://www.ncbi.nlm.nih.gov/pubmed/12699708

Chronic fatigue syndrome: a risk factor for osteopenia?

Abstract:

No data documenting a possible depletion of bone mineral density in patients with chronic fatigue syndrome (CFS) are currently available. However, recent pathophysiological observations in CFS patients may have deleterious consequences on bone density.

Firstly, the deregulation of the 2,5A synthetase RNase L antiviral pathway and its associated channelopathy, implicates increased demands for calcium and consequent increased calcium-re-absorption from the skeletal system.

Secondly, Mycoplasma fermentans which has been frequently associated with CFS, produces a lipopeptide, named 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates macrophages. MALP-2 has been shown to enhance bone resorption in a dose-dependent manner, at least in part by stimulating the formation of prostaglandins.

Thirdly, decreased levels of insulin-like growth factor I (IGF-I) have been reported in CFS-patients. IGF-I is critical to the proliferation of osteoblasts. Consequently, depleted levels of IGF-I may shift the balance between osteoclastic and osteoblastic activity towards bone resorption.

Source: Nijs J, De Meirleir K, Englebienne P, McGregor N. Chronic fatigue syndrome: a risk factor for osteopenia? Med Hypotheses. 2003 Jan;60(1):65-8. http://www.ncbi.nlm.nih.gov/pubmed/12450768

Unconscious amygdalar fear conditioning in a subset of chronic fatigue syndrome patients

Abstract:

Here, a novel hypothesis for chronic fatigue syndrome (CFS) is proposed. CFS may be a neurophysiological disorder focussing on the amygdala. During a ‘traumatic’ neurological event often involving acute psychological stress combined with a viral infection or other chemical or physiological stressor, a conditioned network or ‘cell assembly’ may be created in the amygdala. The unconscious amygdala may become conditioned to be chronically sensitised to negative symptoms arising from the body. Negative signals from the viscera or physiological, chemical and dietary stressors, become conditioned stimuli and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus.

This cell assembly then produces the CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation, leading to sympathetic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. Recovery from CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala’s expressions. I shall firstly discuss predisposing, precipitating, and perpetuating factors involved in the possible etiology of chronic fatigue syndrome (CFS), followed by the patient’s experience of the illness. Finally, I shall look at a suggested explanation for the symptoms of CFS.

Source: Gupta A. Unconscious amygdalar fear conditioning in a subset of chronic fatigue syndrome patients. Med Hypotheses. 2002 Dec;59(6):727-35. http://www.ncbi.nlm.nih.gov/pubmed/12445517