DDPIV/CD26, CXCL12 and CXCR4

CD26: Dipeptidyl Peptidase DPPIV known as adenosine deaminase complexing protein 2 or CD26 is an enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction and apoptosis. CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder.

CXCL12: Stromal-derived-factor-1, SDF-1 also known as C-X-C motif chemokine 12, CXCL12 or Pre-B-Cell Growth-Stimulating Factor. A CXC chemokine that is chemotactic for T-lymphocytes and monocytes. Often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1.

CXCR4: CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes.

Interaction between DPPIV CD26, CXCL12 and CXCR4 is involved in inflammatory diseases.

This was studied in an experimental model of arthritis. Murine antigen-induced arthritis (AIA) induction led to reduced plasma DPPIV CD26 activity. And in CD26-deficient mice, the severity of AIA was increased. CD26-deficient mice exhibited increased levels of circulating active CXCL12, associated with increased numbers of CXCR4-positive cells infiltrating arthritic joints. Decreased circulating CD26 levels in arthritis may influence CD26-mediated regulation of the chemotactic CXCL12/CXCR4 axis.

CD26-deficient mice:
· reduced plasma DPPIV activity↓
· exhibited increased levels of circulating active CXCL12 ↑
· associated with increased numbers of CXCR4-positive cells infiltrating arthritic joints ↑

Reference: Circulating CD26 is negatively associated with inflammation in human and experimental arthritis:

What has that got to do with ME/CFS? The answer is:

Dipeptidyl peptidase IV/CD26 has been evaluated as a biomarker for ME/CFS.

Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26:
In the present study, we found the density of DPPIV/CD26 on lymphocyte surfaces and the concentration of the enzyme in plasma is reduced in CFS subjects, compared to controls. We hypothesize that this reduction is due to chronic lymphocyte activation in CFS patients. The present study adds to the evidence of loss of innate immune function and chronic immune activation, resulting from the long term presence of antigenic stimulus, either self or foreign.

ME/CFS:
· Density of Dipeptidyl Peptidase DPPIV/CD26 on lymphocyte surfaces ↓
· And concentration of the enzyme in plasma ↓
· CXCR4 up-regulated ↑


An up-regulation of CXCR4 in ME/CFS has been shown in other studies:
A gene signature for post-infectious chronic fatigue syndrome

Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Assessment of a 44 Gene Classifier for the Evaluation of Chronic Fatigue Syndrome from Peripheral Blood Mononuclear Cell Gene Expression


The latest Light study Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome showed that mRNA expression for CXCR4 for CFS patient was elevated in relation to healthy controls, but it was not statistic significant. It would be interesting to repeat this Light study with patients after exercise, because exercise-elicited endogenous cortisol effectively augments CXCR4 expression on T lymphocytes. Reference: Cortisol-induced CXCR4 augmentation mobilizes T lymphocytes after acute physical stress


A potential up-regulation of CXCR4 in ME/CFS is worth keeping an eye on because the CXCL12-CXCR4 signaling is involved in both B cell development and development of plasmacytoid dendrite cells:

The Earliest Stages of B Cell Development Require a Chemokine Stromal Cell-Derived Factor/Pre-B Cell Growth-Stimulating Factor

Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling


CXCL12-CXCR4 signaling is also involved in NK development, but it must be noted that nothing is simple in the human body. IL-15 is also involved in NK cell function, and IL15 is low in ME/CFS patients. So how all these factors affect the immune system and the dysregulated NK cells in ME/CFS is not easy to understand:

Differential chemotactic receptor requirements for NK cell subset trafficking into bone marrow

CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice

Mechanistic Model of Natural Killer Cell Proliferative Response to IL-15 Receptor Stimulation


Synovial fluid is a lubricating, nourishing material present in many joints of the body. CXCL12 mediates desensitization of neutrophil respiratory burst in the synovial fluid from Rheumatoid Arthritic Patients.
Reference: Stroma Cell-Derived Factor 1α Mediates Desensitization of Human Neutrophil Respiratory Burst in Synovial Fluid from Rheumatoid Arthritic Patients


Preliminary data from CFS subjects showed differences in neutrophil function based on respiratory burst and phagocytic activity when compared to the control group. These results suggest that differences in neutrophil function in CFS patients may contribute to CFS related immune dysfunction.
Reference: Analysis of Neutrophil Function in Severe and Moderately Affected Chronic Fatigue Syndrome Subjects

This is something I would like to know more about, so...

Let us look for more studies on CD26/CXCR4…

Remember the cancer study: Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults? ME/CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL).

This study Dipeptidyl peptidase IV: serum activity and expression on lymphocytes in different hematological malignancies showed: Significantly decreased serum DPPIV activity and a significant decrease in the percentage of: CD26 + lymphocytes, CD26 + overall white blood cells and lymphocytes in patients with NHL in comparison to healthy controls. The obtained results in the study indicate that immune disturbances that can occur in hematological malignancies might be related to the decreased expression and activity of CD26/DPPIV.

This knowledge has already come to use in this article, Targeting the CD20 and CXCR4 pathways in non-hodgkin lymphoma with rituximab and high-affinity CXCR4 antagonist BKT140: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL.

Data show that Cyclophilin (CYPA) has a critical role in CXCR4 signaling involved in cell proliferation and migration. Reference: Cyclophilin A Is Required for CXCR4-mediated Nuclear Export of Heterogeneous Nuclear Ribonucleoprotein A2, Activation and Nuclear Translocation of ERK1/2, and Chemotactic Cell Migration

And Cyclophilin A is up-regulated in ME/CFS:
A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers

Aberrant CXCR4/CXCL12-mediated inflammatory respons is found in several disorders, such as systemic lupus erythematosus, uveitis, multiple sclerosis and inflammatory bowel diseases. Reference: Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory bowel disease

And dipeptidyl peptidase IV CD26 is reduced in tissue and plasma in active Crohn's disease. This is unlikely to represent simple downregulation induced by inflammation since the key proinflammatory cytokine strongly upregulated DP4 expression in Caco-2 cells.
Reference: Dipeptidyl peptidase-4 expression is reduced in Crohn's disease
Reference: Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease

Data suggest that simultaneous targeting of CXCR4 and CXCR3 may be of benefit in the treatment of the CNS autoimmune disease.
Reference: Antagonism of the chemokine receptors CXCR3 and CXCR4 reduces the pathology of experimental autoimmune encephalomyelitis

This knowledge has led to a Patent application TREATMENT OF AUTOIMMUNE DISEASE where the invention provides methods for identifying a patient suffering from and/or susceptible to autoimmune disease who might be likely to respond to treatment with CXCL12 and/or CXCR4 antagonists. The present invention provides novel CXCL12 and/or CXCR4 antagonists, methods of identifying novel CXCL12 and/or CXCR4 antagonists, and methods involving the use of these in the treatment of autoimmune disease.

The patent application include

Dysautonomia malfunction of the autonomic nervous system, including such disorders as postural orthostatic tachycardia syndrome (POTS); though dysautonomia appears to have multiple causes, post-viral autoimmune damage appears to be a frequent cause.

and

Chronic fatigue immune disorder whose primary symptom is usually intense fatigue; dysfunction syndrome though the syndrome likely has multiple causes, some (CFIDS) maintain that autoimmune damage to the brain stem is the principal mechanism in a significant subset of cases.

Note that POTS is mentioned! And this article suggest that this chemokine CXCR4 may contribute to autonomically mediated pathophysiological events:CXCR4 receptors in the dorsal medulla: implications for autonomic dysfunction

Oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to CXCL12. Low oxygen concentration induces high expression of CXCR4 in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by hypoxia is dependent on both activation of the Hypoxia-inducible factor 1 α and transcript stabilization. In a relay multistep navigation process, the Hypoxia–Hypoxia-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.
Reference: Regulation of the Chemokine Receptor CXCR4 by Hypoxia

And it is hypothesized that autonomic dysfunction/cerebral hypoxia could be involved in ME/CFS. Postural Orhtostatic Tachycardia Syndrome (POTS) is a very common ME/CFS co-morbidity, and POTS-patients are markedly sensitized to hypoxia when upright.
Reference: Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration
Reference: Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity


Chemokines are also involved in pain. Increased signaling by CXCL12 and its receptor, CXCR4, has been shown to contribute to chronic pain behavior. Activation of another chemokine CCR2 by monocyte chemoattractant protein-1 MCP-1 elicits membrane depolarization, trigger action potentials and sensitizes nociceptors via transactivation of transient receptor potential channels TRPA1 and TRPV1.
Reference: Chemokines as pain mediators and modulators.

...there are many puzzle pieces to keep an eye on! Which pieces belong to the ME/CFS puzzle and which pieces do not fit in?

P2X7 in ME/CFS and other diseases

I have previously referred to articles about TRPA1 involvement in inflammation, vasodilation, central sensitization and hypothesized that TRPA1 has a role in ME/CFS/POTS/MCS/pain and more.

TRPA1 is of course only a small part of what is affected in the human body during these diseases. Many other receptors must also be involved. The latest article from Light et al mentions higher expression of P2RX7, so let us take a closer look at the P2X7 receptor.

The P2X7 receptor (P2X7R) is a nonselective cation channel that is activated by extracellular ATP and triggers the secretion of several proinflammatory substances, such as IL-1β, IL-18, TNF-α, and nitric oxide.

Quotes from P2X7 articles:

Following the activation of P2X7R through high concentrations of and/or prolonged exposure to ATP, a large conductance channel is elicited, which leads to dynamic changes in the membrane potential that include an intracellular potassium efflux. This cationic efflux induces inflammasome complex assembly and subsequent pro-caspase-1 maturation into caspase-1 through the NOD-like receptor protein (NLRP3). Caspase-1 plays a key role in the cleavage of pro-IL-1β to form mature IL-1β, which plays a principal role in nitric oxide synthase (NOS), cyclooxygenase-2, and tumor necrosis factor-alpha (TNF-α) activities
Reference: Physiological Roles and Potential Therapeutic Applications of the P2X7 Receptor in Inflammation and Pain

The expression of the purinergic, P2X7 receptor (P2X7R), is known to be enhanced in many brain pathologies where presence of activated microglia is a concurrent feature. This review focuses on the links between P2X7R expression and microglial activation and proliferation. The P2X7R is identified as a key player in the process of microgliosis, where by driving microglial activation, it can potentially lead to a deleterious cycle of neuroinflammation and neurodegeneration.
Reference: Microglia: Proliferation and activation driven by the P2X7 receptor

P2X7 is involved in central sensitization. Purinergic signaling, involving P2X4, P2X7 and P2Y12 receptors, plays a central role in the recruitment and activation of microglia, which have emerged as key regulators of central sensitization.
Reference: Pain hypersensitivity mechanisms at a glance
Reference: Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors
Reference: P2X(7) inhibition in stellate ganglia prevents the increased sympathoexcitatory reflex via sensory-sympathetic coupling induced by myocardial ischemic injury


Lipid rafts are important in the control of nociceptor excitability – P2X7 is associated with lipid rafts

Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered.
Reference: Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability

Reference: Palmitoylation of the P2X7 receptor, an ATP-gated channel, controls its expression and association with lipid rafts
(Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine and less frequently to serine and threonine residues of proteins, which are typically membrane proteins.)

Caveolae are a special type of lipid raft

It has recently been shown in epithelial cells that the ATP-gated ion channel P2X7R is in part, associated with caveolae and colocalized with caveolin-1. In the present study of the mouse heart, we show for the first time, using immunohistochemistry and cryoimmunoelectron microscopy, that P2X7R is expressed in atrial cardiomyocytes and in cardiac microvascular endothelial cells, but not in the ventricle cardiomyocytes. In cardiac tissue homogenates derived from caveolin-1 deficient mice (cav-1-/-), an increase of the P2Xrx7 mRNA and P2X7R protein (80 kDa) was found, particularly in atrial samples.
Reference: Increased P2X7R expression in atrial cardiomyocytes of caveolin-1 deficient mice

Some guessing:
Some ME patients have POTS. POTS patients may have autoimmunoreactive IgGs against proteins associated with caveolae structure. Cavelolin-1 is a protein in the caveolae. Increased P2X7R expression is found in atrial cardiomyocytes of caveolin-1 deficient mice. ME patients show increased P2RX7 expression.

P2X7 and motor neruron death/cell death:

Here we found that P2X(7) receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death
Reference: Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis

P2X7-induced motor neuron death was dependent on neuronal nitric oxide synthase-mediated production of peroxynitrite, p38 activation, and autocrine FAS signaling. Taken together, our results indicate that motor neurons are highly sensitive to P2X7 activation, which triggers apoptosis by activation of the well-established peroxynitrite/FAS death pathway in motor neurons.
Reference: P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway

A cytofluorometric assay demonstrated that P2X7 activation induced ROS formation in EOC13 cells, via a mechanism independent of Ca2+ influx and K+ efflux. Cytofluorometric measurements of Annexin-V binding and 7AAD uptake demonstrated that P2X7 activation induced EOC13 cell death. The ROS scavenger N-acetyl-L-cysteine impaired both P2X7-induced EOC13 ROS formation and cell death, suggesting that ROS mediate P2X7-induced EOC13 death. In conclusion, P2X7 activation induces the uptake of organic cations, ROS formation, and death in EOC13 microglia.
Reference: P2X7 Receptor Activation Induces Reactive Oxygen Species Formation and Cell Death in Murine EOC13 Microglia

Let us keep an eye on P2X7 and ME/CFS research to find out what the higher expression of P2RX7 actually means in ME/CFS.

Update: 
Surface expression of P2X7R on PBMC in patients with pSS was significantly higher than controls, suggesting P2X7R may contribute to the complex pathogenesis of pSS and also anxiety and/or depression.
Reference: The expression of P2X7 receptors on peripheral blood mononuclear cells in patients with primary Sjögren's syndrome and its correlation with anxiety and depression

Transducer and amplifier in ME/CFS/MCS/pain?

From the world of electronic device we know the terms “transducer” and “amplifier”:

A transducer is a device that converts a signal in one form of energy to another form of energy. Energy types include (but are not limited to) electrical, mechanical, electromagnetic (including light), chemical, acoustic or thermal energy. Reference: Transducer

An amplifier is an electronic device that increases the power of a signal. It does this by taking energy from a power supply and controlling the output to match the input signal shape but with a larger amplitude. In this sense, an amplifier modulates the output of the power supply. Reference: Amplifier

The electronic device is connected by wires.

There are also “transducers”, “amplifiers” and “wires” in the human body:

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye, and odorants binding to odorant receptors in the nasal epithelium. The sensory transduction is the conversion of a sensory stimulus from one form to another. Transduction in the nervous system typically refers to stimulus alerting events wherein a physical stimulus is converted into an action potential, which is transmitted along axons towards the central nervous system where it is integrated. A receptor cell converts the energy in a stimulus into a change in the electrical potential across its membrane. It causes the depolarization of the membrane to allow the action potential to be transducted to the brain for integration. Reference: Signal transduction Transduction (physiology)

The human “transducers” are the sensory receptors and the human “wires” are called neurons, axons and sensory fibers/ afferent nerve fibers. Just outside the spinal cord, thousands of afferent neuronal cell bodies are aggregated in a swelling in the dorsal root known as the dorsal root ganglion. Reference: Wikipedia.

When a ME patient no longer can tolerate sunlight, soft music, the smell of toothpaste or the weight from a blanket something must be wrong with the transducers, the amplifiers and/or the wires.

To understand the disease and the symptoms we must locate and identify the problem in the transducers, the amplifiers and/or the wires in the body.

Is there a defective amplifier in the dorsal root ganglion? In the brain? Is it out of order because of an autoimmune attack? An autoimmune attack on a receptor? Is there a domino effect involved?

I am looking for answers. Am I getting closer? Is TRPA1 involved? TRPA1 amplifies pain and inflammation. What amplifies light, sound, odor and touch?

TRPA1 - A Transducer and Amplifier of Pain and Inflammation

Excessive activation of TRPA1 and TRPV1 by ROS may induce central sensitization – does it concern ME?

Is TRPV4 involved? TRPC3? P2X3? Articles from a google-brainstorm on the subject:

Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia
(remember Ian Lipkin’s results: IL-17 is up-regulated in spinal cord fluid in ME/CFS patients)

Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons

Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model

P2X3 receptor: a novel ‘CASKade’ of signaling?

Identification of voltage-gated K+ channel beta 2 (Kvβ2) subunit as a novel interaction partner of the pain transducer Transient Receptor Potential Vanilloid 1 channel (TRPV1)

Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling

TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells

Potentiation of acid-sensing ion channel activity by the activation of 5-HT₂ receptors in rat dorsal root ganglion neurons

Methods of antagonizing signal transduction in dorsal root ganglion cells

Autoimmune Autonomic Neuropathy

Acetylcholine is one of many neurotransmitters in the autonomic nervous system.

Acetylcholine receptors are subdivided into muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors, while the nicotinic acetylcholine receptors are ligand-gated ion channels. There are 5 muscarinic receptors and 17 nicotinic acetylcholine receptors .

One of these receptors, ganglionic (α3) acetylcholine receptor (AChR), is a target for auto antibodies resulting in autonomic dysfunction.

Autonomic dysfunction associated with ganglionic antibody is called autoimmune autonomic ganglionopathy (AAG), but has been replaced by the term autoimmune autonomic neuropathy (AAN).

Autoimmune autonomic neuropathy is mentioned as new diagnosis in ICD11 Beta Draft:

7N36.1 Autoimmune autonomic neuropathy, ganglionic acetylcholine receptor antibody positive

7N37.1 Limited autoimmune autonomic neuropathy: ganglionic acetylcholine receptor antibody positive

Lower G-AchR antibodies titers are often associated with either subacute-chronic variants of autonomic neuropathy or limited forms of autonomic neuropathy. Reference: Other autonomic neuropathies associated with ganglionic antibody

Autoimmune autonomic ganglionopathy is a clinically heterogeneous disease with variable presentation, particularly in subjects with lower antibody titers. Reference: Antibody titers predict clinical features of autoimmune autonomic ganglionopathy

Patients with primary autonomic neuropathies might manifest restricted forms of autonomic dysfunctions, such as cholinergic dysautonomia, postural orthostatic tachycardia syndrome and diffuse sympathetic and parasympathetic dysfunctions. Orthostatic symptoms are common, and they can be accompanied by syncope. Chronic progression is possible. Reference: Wide range of clinicopathological features in immune-mediated autonomic neuropathies

Reversible cognitive impairment is independently associated with both orthostatic hypotension and elevated nicotinic acetylcholine receptor autoantibodies, thereby expanding the clinical spectrum of autonomic ganglionopathy and, in so doing, providing an additional treatable cause of cognitive impairment. Reference: Autoimmune autonomic ganglionopathy with reversible cognitive impairment


More articles on the subject:

Postural orthostatic tachycardia syndrome: the Mayo clinic experience

Treatment-responsive pandysautonomia in an adolescent with ganglionic α3-AChR antibodies

Autoantibody-induced internalization of nicotinic acetylcholine receptor α3 subunit exogenously expressed in human embryonic kidney cells

Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice

Sudomotor dysfunction in autoimmune autonomic ganglionopathy

Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy

Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments

Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy

Passive Transfer of Autoimmune Autonomic Neuropathy to Mice

Ganglionic Acetylcholine Receptor Autoantibody:Oncological, Neurological, and Serological Accompaniments

Autonomic Involvement in Subacute and Chronic Immune-Mediated Neuropathies

TRPA1 and migraine - ME and migraine

I have previously referred to papers about TRPA1 involvement in inflammation, vasodilation, central sensitization and hypothesized that TRPA1 has a role in ME/CFS/POTS/MCS/fibromyalgia and more.

I have mentioned TRP in irritant-induced headache in MCS: Transient Receptor Potential in Multiple Chemical Sensitivity

And with this paper: TRPA1 and other TRP channels in migraine I will ad migraine to my list of TRPA1-suspicions in ME.

Many ME/CFS/MCS patients do have migraine. And the article states: "The ability of TRPA1 to sense and to be activated by an unprecedented series of exogenous and endogenous reactive molecules has now been extensively documented. Several of the TRPA1 activators are also known as triggers of migraine attack. Thus, TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine pathophysiology and as possible new targets for its treatment."

And:

"Emerging information on TRP channels, and particularly TRPA1, which, targeted by migraine triggers, contribute, by activating the trigeminal CGRP-dependent pathway, to the genesis of pain and the accompanying symptoms of the attack, seems to be of paramount importance to solve what still remains the enigma of the migraine mechanism."

Excessive activation of TRPA1 and TRPV1 by ROS may induce central sensitization – does it concern ME?

Researchers from Japan have made a study to clarify how reactive oxygen species (ROS) impact on synaptic transmission.  They investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings:

Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels

They wanted to understand more about central neuropathic pain (CNP) in the spinal cord such as chronic pain after spinal cord injury (SCI). It is known that ROS is involved, but how?

The results were:

·         ROS enhance excitatory synaptic transmission in rat spinal dorsal horn neurons.

·         These excitatory effects are induced by the activation of TRPA1 and TRPV1 channels.

·         ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons.

·         ROS in the spinal cord can play an important role in central sensitization and result in chronic pain.

And the conclusion was: “This is the first report to show that ROS enhance excitatory synaptic transmission in rat spinal dorsal horn neurons via TRPA1 and TRPV1 channels. Our results suggest that ROS play an important role in the activation of SG neurons and provide insight into our understanding of the mechanisms of CNP in the spinal cord, such as that following SCI.”

I was very excited when I read that, because it is hypothesized that central sensitization is involved in ME/CFS and the co-morbidities Multiple Chemical Sensitivity (MSC) and fibromyalgia.

And furthermore, I have my own hypothesis that the ME/CFS co-morbidity Postural Orthostatic Tachycardia Syndrome also fit in. And it all come down to TRPA1 activation.

The next step in my hypothesis is that nitric oxide (nitrosative stress/mitochondrial dysfunction?) and an autoimmune attack also are involved. Something must keep those TRPA1s going!

The Japanese researchers mentioned some other studies:

·         A number of reports had shown that the major sources of ROS are dorsal root ganglion (DRG) neurons and microglia in the spinal cord.

·         A group reported that reactive nitrogen species (RNS), especially peroxynitrite, contribute to central neuropathic pain in the spinal cord.

·         ROS convert polyunsaturated fatty acids into α,β-unsaturated aldehydes, which activate TRPA1 channels.

They also pointed out that in addition to ROS, RNS (peroxynitrite) may also have enhanced the excitatory postsynaptic currents in the present study.

And ROS induce inward currents in SG neurons via TRPA1 channels, and a previous study has shown that inward currents are also involved in NMDA receptor activation.

The good news is that the effect of ROS exposure is reversible, and the bad news is that long-term exposure to ROS has the potential to elicit plastic changes in the neurons.

I think the mechanisms described in this fine study could be used to explain some of the biochemistry that has gone bad in ME.

ROS (TRPA1 activation) after an inflammatory response will resolve. But sustained ROS (TRPA1 activation) could be plastic changes in the neurons or it could be sustained by some auto antibody. And perhaps some yet to be discovered auto antibody is involved.

Could auto antibodies be involved in spinal cord injury??? Look what I found:

Roles of Autoantibodies in Central Nervous System Injury:

“Stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) cause irreversible damage to the nervous system. Although these are neurological disorders, pathology and loss of function also occur outside the nervous system and are often not easily explained by paralysis or impaired neural function. Emerging data indicate that much of the pathological sequelae that accompanies CNS trauma has characteristics of a self-directed immunological disease. Here, we outline those data, describing basic mechanisms of B cell activation and autoantibody synthesis after CNS injury. A summary of the anti-CNS autoantibodies that have been identified in humans and animals is provided along with a discussion of how autoantibodies may affect survival of neuronal and non-neuronal tissues and whether autoimmune reactions are feasible therapeutic targets after CNS trauma.”

And it becomes even more exciting because this articles

Orthostatic hypotension following spinal cord injury: understanding clinical pathophysiology

states that:

“Over time (days to weeks) the spinal shock resolves, but Spinal Cord Injury patients are frequently troubled with sudden falls in blood pressure upon postural change, or following prolonged periods of sitting (orthostatic hypotension) characterised by dizziness, lightheadedness or even syncopal events.”

If the orthostatic hypotension occurs right after injury, it could be ROS (TRPA1 activation) because of inflammation, if it continues, could it be auto antibodies? (I am just guessing)

I have already mentioned TRPA1’s role in blood pressure and possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders: TRPA1 involvement in autonomic dysfunction in ME?

Do you follow my chain of thoughts? Or else, please continue reading:

Caveolae, eNOS and TRPA1?

Does excessive activation of TRPA1 and TRPV1 by ROS concern ME?

Ligheder mellem ME/CFS og sclerose

Gerwyn Morris and Michael Maes har skrevet denne spændende artikel, hvor de sammenligner ME/CFS med sclerose og finder en masse ligheder:

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

• Invaliderende træthed
• Udpræget intolerance over for motion
• Ortostatisk intolerance
• Postural hypotension
• Flere sammenfaldende dysreguleringer i immunforsvaret
• Kronisk inflammation
• Kronisk ”cellestress” (elevated oxidative and nitrosative stress)
• Reduceret niveau af antioxidanten glutathione
• Forøget antal B lymfocytter
• Påvisning af en lang række auto antistoffer (tegn på autoimmun aktivitet)
• Begge sygdomme kan bedres af medicinen Rituximab, som fjerner B lymfocytterne. En behandling der anvendes til autoimmune sygdomme og visse former for kræft.

 

Dettevar blot et lille udpluk at de fællestræk, som artiklen påviser. Klik ind og kig artiklen igennem. Sammenligningerne er sat op i  tabeller, så det er nemt at overskue, selvom man ikke gider læse hele artiklen.