In my previous blog posts I referred to articles that make it plausible that TRPA1 is involved in the biochemistry of co-morbid ME conditions like Multiple Chemical Sensitivity and inflammation/pain.
But what about autonomic dysfunctions like Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance? Is there a connection? Is TRPA1 involved in regulation of the vasculature?
The answer is: YES, TRPA1 and other TRP channels have influence on regulation of the vasculature.
My favorite article today is this one:
Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo
The conclusion from this article:
“TRPA1 is involved in mediating vasodilation. TRPA1 can also influence changes in blood pressure of possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders.”
There are other fine articles describing TRP in the vasculature:
TRPA1 channels in the vasculature
Transient receptor potential channels and vascular function
Cerebral Blood Flow and TRP
We already know that Cerebral Blood Flow is disturbed in ME/CFS patients:
Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling
Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome
…and these articles describe the connection between TRP and Cerebral Blood Flow:
Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow
Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels
The connection between chemical sensitivity, TRPA1 and cerebral blood flow
TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation
onsdag den 13. februar 2013
mandag den 11. februar 2013
TRPA1/TRPV4/PAR in inflammation/pain
Injury and inflammation trigger the activation of proteases from the circulation, immune cells and epithelial tissues that regulate cells by cleaving protease-activated receptors (PARs), members of a family of four G protein coupled receptors (GPCRs).
These G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain.
PAR2 is co-expressed with substance P and calcitonin gene-related peptide by a subpopulation of primary spinal afferent neurons that control neurogenic inflammation and pain transmission. Activation of PAR2 on sensory nerve endings evokes the local release of these neuropeptides, which stimulate extravasation of plasma proteins, infiltration of neutrophils and vasodilation (neurogenic inflammation). PAR2 activation also promotes the central release of neuropeptides that activate second order spinal neurons that transmit pain. These mechanisms contribute to painful inflammation of the intestine, pancreas and joints. Therefore, it is of considerable interest to understand the mechanisms by which PARs regulate the activity of nociceptive neurons.
Members of the TRP family, including TRPV1, TRPV4 and TRPA1 mediate neurogenic inflammation and pain, and are major down-stream targets of PAR2 . Activation of these non-selective cation channels stimulates the influx of extracellular Ca2+ ions and the release of neuropeptides in peripheral tissues and the spinal cord, which induces neurogenic inflammation and pain. During injury and inflammation, several factors are generated that can directly activate these channels. Elevated temperatures, protons and lipid mediators activate TRPV1, mechanical shear stress, osmotic stimuli and lipid mediators activate TRPV4, and products of reactive oxygen species and reactive prostaglandin metabolites activate TRPA1. However, indirect mechanisms, particularly those triggered by GPCRs, play a prominent role in TRP channel activation. Many GPCRs that induce neurogenic inflammation and pain indirectly regulate TRP channels, which mediate their pro-inflammatory and pronociceptive actions.
Reference: Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) Coupling is Required for Sustained Inflammatory Signaling
I think it is of particular interest, that TRP can be activated of Reactive Oxygen Species (ROS), because oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms
Some researchers believe that ME/CFS, fibromyalgia, irritable bowel syndrome and other pain syndromes share a common biochemistry via sensitization. This review article describes TRPA1 mediated neural cross-talk induced by oxidative stress as model for some pain syndromes:
TRPV1 and TRPA1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons.
Peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously.
The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk.
Reference: Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome
A thorough description of ROS and TRP is provided in this article:
Role of Reactive Oxygen Species and Redox in Regulating the Function of Transient Receptor Potential Channels
And further description of peripheral sensitization influenced by chemokines/TRP activation is found in this article: Chemokines as Pain Mediators and Modulators
This knowledge opens the possibility that TRPA1 antagonist can be used against inflammatory pain:
Patent application: NOVEL TRPA1 ANTAGONISTS
These G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain.
PAR2 is co-expressed with substance P and calcitonin gene-related peptide by a subpopulation of primary spinal afferent neurons that control neurogenic inflammation and pain transmission. Activation of PAR2 on sensory nerve endings evokes the local release of these neuropeptides, which stimulate extravasation of plasma proteins, infiltration of neutrophils and vasodilation (neurogenic inflammation). PAR2 activation also promotes the central release of neuropeptides that activate second order spinal neurons that transmit pain. These mechanisms contribute to painful inflammation of the intestine, pancreas and joints. Therefore, it is of considerable interest to understand the mechanisms by which PARs regulate the activity of nociceptive neurons.
Members of the TRP family, including TRPV1, TRPV4 and TRPA1 mediate neurogenic inflammation and pain, and are major down-stream targets of PAR2 . Activation of these non-selective cation channels stimulates the influx of extracellular Ca2+ ions and the release of neuropeptides in peripheral tissues and the spinal cord, which induces neurogenic inflammation and pain. During injury and inflammation, several factors are generated that can directly activate these channels. Elevated temperatures, protons and lipid mediators activate TRPV1, mechanical shear stress, osmotic stimuli and lipid mediators activate TRPV4, and products of reactive oxygen species and reactive prostaglandin metabolites activate TRPA1. However, indirect mechanisms, particularly those triggered by GPCRs, play a prominent role in TRP channel activation. Many GPCRs that induce neurogenic inflammation and pain indirectly regulate TRP channels, which mediate their pro-inflammatory and pronociceptive actions.
Reference: Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) Coupling is Required for Sustained Inflammatory Signaling
I think it is of particular interest, that TRP can be activated of Reactive Oxygen Species (ROS), because oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms
Some researchers believe that ME/CFS, fibromyalgia, irritable bowel syndrome and other pain syndromes share a common biochemistry via sensitization. This review article describes TRPA1 mediated neural cross-talk induced by oxidative stress as model for some pain syndromes:
TRPV1 and TRPA1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons.
Peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously.
The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk.
Reference: Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome
A thorough description of ROS and TRP is provided in this article:
Role of Reactive Oxygen Species and Redox in Regulating the Function of Transient Receptor Potential Channels
And further description of peripheral sensitization influenced by chemokines/TRP activation is found in this article: Chemokines as Pain Mediators and Modulators
This knowledge opens the possibility that TRPA1 antagonist can be used against inflammatory pain:
Patent application: NOVEL TRPA1 ANTAGONISTS
Transient Receptor Potential in Multiple Chemical Sensitivity
I have previously written about Transient Receptor Potential Ion Channels, because they are mentioned in research on ME/CFS and co-morbid conditions.
TRP is also involved in chemosensation and maybe in Multiple Chemical Sensitivity (MSC).
TRPA1/TRPV1 in chemosensation
Transient Receptor Potential Ankyrin 1 (TRPA1) is a member of the TRP family. TRPA1 function as a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species and noxious constituents of smoke and smog, initiating irritation and airway reflex responses.
Together with Transient Receptor Potential Vanilloid 1 (TRPV1), TRPA1 may contribute to chemical hypersensitivity, chronic cough and airway inflammation in asthma.
Trigeminal chemosensory nerve endings in the nasal mucosa are in the first line of defense against noxious chemical challenges.
TRPA1 is expressed in 20–36.7 percent of trigeminal neurons, 20–56.5 percent of dorsal root ganglion neurons, and 28.4 percent of neurons in nodose ganglia.
Neuropeptides such as Substance P and Calcitonin Gene Related Peptide (CGRP), released from chemically stimulated nerve endings, promote neurogenic inflammatory vasodilation and leakage, contributing to narrowing or obstruction of the nasal passages.
Since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond much more strongly. With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity. This cumulative effect may result in robust TRPA1-induced irritation even at low sub-acute exposure levels, for example during periods of increased photochemical smog exposures, or low level indoor air pollution. Once irreversibly modified, channels may remain active for extended periods of time even when the irritant stimulus is removed.
(I think it is interesting that TRPA1 reacts more strongly when glutathione is depleted, because a study found decreased levels of cortical glutathione in CFS patients )
Reference: Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control
Reference: Chapter 11 TRPA1 : A Sensory Channel of Many Talents
Research on this topic is to be found in the Project Reporter from National Insitutes of Health
Project Leader Gerry Oxford has this project:
ROLE OF TRP CHANNELS IN ENVIRONMENTAL IRRITANT-INDUCED HEADACHE DESCRIPTION
“Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple Chemical Sensitivity (MCS).”
“It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium.In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms.”
The knowledge about TRPA1 is used in a patent application:
Treatment of Respiratory Disorders using TRPA1 Antagonists
TRP is also involved in chemosensation and maybe in Multiple Chemical Sensitivity (MSC).
TRPA1/TRPV1 in chemosensation
Transient Receptor Potential Ankyrin 1 (TRPA1) is a member of the TRP family. TRPA1 function as a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species and noxious constituents of smoke and smog, initiating irritation and airway reflex responses.
Together with Transient Receptor Potential Vanilloid 1 (TRPV1), TRPA1 may contribute to chemical hypersensitivity, chronic cough and airway inflammation in asthma.
Trigeminal chemosensory nerve endings in the nasal mucosa are in the first line of defense against noxious chemical challenges.
TRPA1 is expressed in 20–36.7 percent of trigeminal neurons, 20–56.5 percent of dorsal root ganglion neurons, and 28.4 percent of neurons in nodose ganglia.
Neuropeptides such as Substance P and Calcitonin Gene Related Peptide (CGRP), released from chemically stimulated nerve endings, promote neurogenic inflammatory vasodilation and leakage, contributing to narrowing or obstruction of the nasal passages.
Since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond much more strongly. With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity. This cumulative effect may result in robust TRPA1-induced irritation even at low sub-acute exposure levels, for example during periods of increased photochemical smog exposures, or low level indoor air pollution. Once irreversibly modified, channels may remain active for extended periods of time even when the irritant stimulus is removed.
(I think it is interesting that TRPA1 reacts more strongly when glutathione is depleted, because a study found decreased levels of cortical glutathione in CFS patients )
Reference: Chapter 11 TRPA1 : A Sensory Channel of Many Talents
Research on this topic is to be found in the Project Reporter from National Insitutes of Health
Project Leader Gerry Oxford has this project:
ROLE OF TRP CHANNELS IN ENVIRONMENTAL IRRITANT-INDUCED HEADACHE DESCRIPTION
“Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple Chemical Sensitivity (MCS).”
“It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium.In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms.”
The knowledge about TRPA1 is used in a patent application:
Treatment of Respiratory Disorders using TRPA1 Antagonists
mandag den 7. januar 2013
ME/CFS Research at a Glance
When reading these short statements (quotes) about ME/CFS, please, be aware of this: ME/CFS diagnosis used in the different studies can be based on different diagnosis criteria. And short statements like these can be misguiding, so please read the full reference before using any of the statements. Each statement is a result of a single study and further studies are necessary to confirm data. The statements below are only meant to be an appetizer for further reading.
Dysregulation of the immune system
Data suggested significant dysregulation of the immune system in ME/CFS patients: Significant increases in IL-10, IFN-γ, TNF-α, CD4+CD25+ T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8+T cells and NK phenotypes, in particular the CD56bright NK cells was significantly decreased. Granzyme A and granzyme K expression was reduced while expression levels of perforin were significantly increased.[1]
NK cytotoxic activity was significantly decreased in the ME/CFS patients at baseline (T1), 6 month (T2) and 12 month (T3) compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the ME/CFS group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-γ and TNF-α at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non-fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to T1 and T3. These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore, NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study.[2]
There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the ME/CFS sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 were significantly decreased in NK cells. Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in ME/CFS patients.[3]
In a study approximately 1.2 million cancer cases and 100,000 controls (age range, 66-99 years; 1992-2005) were evaluated: CFS was associated with an increased risk of non-Hodgkin lymphoma. Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma, marginal zone lymphoma and B cell NHL not otherwise specified.[4]
There is prolonged elevated antibody level against the encoded proteins Epstein Barr Virus dUTPase and Epstein Barr Virus DNA polymerase in a subset of CFS patients, suggesting that this antibody panel could be used to identify these patients, if preliminary findings are corroborated by studies with a larger number of EBV subset CFS patients.[5]
A study showed changes in B cells in CFS patients - a subtle tendency to autoimmunity? CFS patients had greater numbers of naïve B-cells as a % lymphocytes - 6.3 % versus 3.9 % in healthy controls (P=0.034), greater numbers of naïve B-cells as a % of B-cells - 65 % versus 47 % in controls (P=0.003), greater numbers of transitional B-cells - 1.8 % versus 0.8 % in controls (P=0.025) and reduced numbers of plasmablasts - 0.5 % versus 0.9 % in controls (P=0.013).[6]
Treatment
In a double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003).[7]
A study examined the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating ME/CFS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating ME/CFS. Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted exercise tolerance (ET) 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022).[8]
Researchers hypothesized that subset classification of Epstein-Barr virus (EBV) in chronic fatigue syndrome (CFS) is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed. After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.[9]
Gene expression
A study examined metabolite-detecting (ASIC3, P2X4 and P2X5 receptors, and TRPV1), adrenergic (α-2a, β-1, and β-2 receptors and catechol-O-methyltransferase), and immune (CD14, TLR4, IL-6, IL-10, and lymphotoxin α) gene expression (mRNA) in patients with CFS versus patients with multiple sclerosis (MS) versus healthy controls and determined their relationship to fatigue and pain before and after exercise: Patients with CFS had greater postexercise increases in fatigue and pain and greater mRNA increases in P2X4 receptor, TRPV1, CD14, and all adrenergic receptors than controls. Patients with CFS with comorbid fibromyalgia also showed greater increases in ASIC3 and P2X5 receptors. Patients with MS had greater postexercise increases than controls in β-1 and β-2 adrenergic receptor expressions and greater decreases in TLR4. In MS, IL-10 and TLR4 decreases correlated with higher fatigue scores.[10]
Postural orthostatic tachycardia syndrome (POTS) – NOT ME/CFS research, but research in a co-morbidity
ME/CFS is suspected to be an autoimmune disease. And the ME/CFS co-morbidity, POTS, is also suspected to be autoimmune:
A study from Mayo Clinic: 152 patients were identified with POTS. Ganglionic acetylcholine receptor antibody was detected in 14.6%, suggesting an autoimmune origin in at least 1 in 7 patients.[16]
Another study from Mayo Clinic: Autoantibodies are present in patients with POTS. These autoantibodies cross-react with a wide range of cardiac proteins and may induce alterations in cardiac function. (Forty unique proteins were identified and these include proteins that are associated with cardiac hypertrophy (mimecan, myozenin), cardiac remodeling (periostin), cardiomyopathy (desmin, desmoplakin), cell survival (laminin), structural integrity (filamin), chaperone proteins (crystalline, HSP70), mitochondrial enzymes, and channel proteins.) Autoimmune pathogenetic mechanisms should be further explored in these patients.[17]
And if we look further, orthostatic intolerance might be a significant feature of autonomic nervous system dysfunction in patients suffering from mitochondrial cytopathy.[18]
Orthotstatic hypotension is also suspected to be connected to autoantibodies:
Orthostatic hypotension (OH) is characterized by an abnormal autonomic response to upright posture. Activating autoantibodies to β1/2-adrenergic (AAβ1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH.[19]
Vasodilatory autoantibodies to adrenergic β2 receptor and muscarinic receptor (M3) are present in a high proportion of orthostatic hypotension (OH) patients with and without apparent autonomic dysfunction suggests that these autoantibodies may cause or exacerbate orthostasis by altering the compensatory postural vascular response.[20]
Left ventricular dysfunction
Antibodies against cholinergic and adrenergic receptors seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion.[21] It could be interesting to look for such auto antibodies in ME/CFS, because left ventricular dysfunction is seen in ME/CFS patients:
Compared to controls, the CFS group had substantially reduced left ventricular mass (reduced by 23%), end-diastolic volume (30%), stroke volume (29%) and cardiac output (25%).[22]
Cardiac dysfunction with low cardiac output due to small left ventricular chamber may contribute to the development of chronic fatigue as a constitutional factor in a considerable number of CFS patients.[23]
In this study, the researcher report the occurrence of mild left ventricular dysfunction in 8 of 60 patients in continuing studies of this population with CFS, younger than 50 years old, and with no risk factors for coronary artery disease.[24]
Mitochondrial dysfunction
A study showed that, ME/CFS patients have measureable mitochondrial dysfunction which correlates with the severity of the illness.[25]
138 ME/CFS patients attended a private practice and took the ATP Profile biomedical test. The results revealed that all of these patients had measureable mitochondrial dysfunction. Mitochondrial function is typically impaired in two ways: substrate or co-factor deficiency, and inhibition by chemicals, exogenous or endogenous.[26]
Increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP are found in ME/CFS. This leads researchers to hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS.[27]
Auto antibodies found in ME/CFS
Examination of anticardiolipin antibodies (ACAs) in the sera of patients clinically diagnosed with chronic fatigue syndrome (CFS) using an enzyme-linked immunoassay procedure demonstrated the presence of immunoglobulin M isotypes in 95% of CFS serum samples tested. The presence of immunoglobulin G and immunoglobulin A isotypes were also detected in a subset of the samples. Future studies will focus on elucidating whether alterations to mitochondrial inner membranes and/or metabolic functions play a possible role in the expression of ACAs.[28]
A PET study to demonstrated a reduction of neurotransmitter receptor binding in brains of CFS patients with high levels of serum autoantibody. The present results suggest the possibility of the autoantibody interacting directly with the mAChR in the brain, although the autoantibody at this level did not affect cognitive function in CFS patients. The present finding supports the idea that penetration of the antibody into the brain resulted in impaired BBB function. This may be one possible mechanism by which the serum autoantibody could affect central mAChR function.[29]
Autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1) were detected in a large number of CFS patients and were related to CFS symptoms. The findings suggested that subgroups of CFS are associated with autoimmune abnormalities of CHRM1. [30]
References:
[1] Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
[2] Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis
[3] Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
[4] Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults
[5] Martin Lerner: Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset
[6] Altered functional B-cell subset populations in patients with chronic fatigue syndrome compared to Healthy Controls
[7] Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study
[8] A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome
[9] Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up
[10] Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls
[11] Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome
[12] Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes
[13] Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome
[14] Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome
[15] Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome
[16] Postural orthostatic tachycardia syndrome: the Mayo clinic experience
[17] Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome
[18] Dysfunction Presenting as Orthostatic Intolerance in Patients Suffering From Mitochondrial Cytopathy http://www.ncbi.nlm.nih.gov/pubmed/20960537
[19] Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an "autoimmune" orthostatic hypotension.
[20] Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism
[21] Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function
[22] Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging
[23] Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome
[24] Repetitively negative changing T waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome. Left ventricular dysfunction in a cohort
[25] Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
[26] Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit
[27] Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)
[28] Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome
[29] Reference: Reduction of [(11)C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor
[30] Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome
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