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.

Første resultater fra Ian Lipkin's store ME/CFS studie

Der er nyheder fra et studie udført af den berømte, anerkendte professor Ian Lipkin, direktør for Center for Infektion og Immunologi ved Columbia Universitet i USA. Studiet omhandler mulige virus og immundysfunktioner involveret i  Myalgic encephalomyelitis / Chronic Fatigue Syndrome  (ME/CFS).

Studiet er ikke afsluttet, men professor Ian Lipkin har oplyst om nogen af de vigtigste resultater.

Der er ikke fundet aktiv virusinfektion i ME/CFS. ME/CFS starter ofte efter en virusinfektion, så der muligvis tale om en ”hit and run” effekt.

Undersøgelserne af ME/CFS patienterne viste, at der var tydelig forskel på ny-syge og patienter, der havde haft sygdommen i årevis. Ian Lipkin satte en grænse ved 3 år. Det kan betyde, at der skal være forskel på de immunologiske markører, der skal anvendes til patienter, der har haft sygdommen i kortere tid (under 3 år), og de der har haft sygdommen i mange år (over 3 år).  

I gruppen af ME/CFS patienter, der havde været syge kortere tid fandt man øget antal eosinofile leucocytter, og et anderledes cytokin mønster end hos ME/CFS patienter, der havde været syge i lang tid.  

Ændringer i cytokin mønsteret er relevant, fordi der findes medicin, der kan regulere dette. Det vil naturligvis ikke kunne helbrede ME/CFS, men måske kunne mindske nogle af de symptomer, som patienterne har.

F. eks. blev det påvist, at IL-17 var forhøjet hos ME/CFS patienter, der havde været syge mindre end 3 år.  Og der findes faktisk medicin målrettet dette interleukin. Det betyder naturligvis ikke, at patienter skal begynde at forsøge sig med nogen former for medicin. Men det betyder, at man skal prøve at få lægerne til at måle på dette, så der kan opsamles flere måleresultater og viden om sygdommen ME/CFS. Og så kan der på sigt foretages kliniske afprøvninger af medicinen.

Dette var fund i blodprøverne. I studiet havde man også undersøgt rygmarvsvæske. Her fandt man forhøjede niveauer af Th-2 cytokinerne kaldet IL-10 og IL-13. Der var også et forhøjet niveau af Th-1 cytokinerne IL-1beta, IL-5, TNF-alfa og IL-17. Ian Lipkin fraråder, at patienterne selv henvender sig til lægen og forsøger at få dette undersøgt. Man er nødt til at afvente forskningen og finde ud af hvad denne immun dysregulering betyder.

(Hvis man vil have lidt baggrundsviden om immunsystemet og Th1/Th2, så vil jeg anbefale, at man læser Professor Klaus Bendtzens artikel Immunsystemet ved kronisk inflammation)

Forskningen fortsætter, så det bliver spændende, når der engang udkommer en artikel med resultaterne, og forhåbentligt et bud på en immunologisk biomarkør til ME/CFS. Jeg kan anbefale, at man går ind og læser hele Ian Lipkins fremlæggelse. Den findes på Phoenix Rising’s Blog Lipkin finds biomarkers not bugs

Cort Johnson har også skrevet et referat på Simmaron Research Foundation’s hjemmeside: Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

Hvad er bakteriel translokation?

Ved bakteriel translokation forstås almindeligvis passagen af bakterier over tarmvæggen til mesenteriske lymfeknuder og det systemiske kredsløb.

Utæt tarm (leaky gut) og en mild grad af bakteriel translokation er sat i forbindelse med ME/CFS patienter. En søgning i pubmed database på bakteriel translokation i ME/CFS giver 7 artikler, der beskriver problematikken. Der er også enkeltstående beretninger om en bedring af sygdomssymptomer hos ME/CFS patienter, når den bakterielle translokation reduceres.

Det er ikke lykkedes for mig at finde dansk litteratur om bakteriel translokation i ME/CFS. Imidlertid fandt jeg denne artikel, der skriver om bakteriel translokation i hos patienter med levercirrose:

Antibiotika bedrer de cirkulatoriske forhold hos patienter med levercirrose

Her er problemet med bakteriel translokation af omfattende grad og må ikke umiddelbart sammenlignes med problematikken i ME/CFS. Men artiklen er god, fordi den beskriver begrebet bakteriel translokation:

Translokation af bakterielt DNA er en dynamisk proces, hvor mængden af DNA-materiale varierer over tid hos den enkelte patient. Bakterielt DNA menes i sig selv at kunne stimulere et inflammatorisk respons ved frigørelse af tumornekrosefaktor alfa (TNFalfa) og interleukiner. Det inflammatoriske respons’ sværhedsgrad er parallelt med serum-DNA-niveauet og kan nå et niveau, som det ses ved spontan bakteriel peritonitis. Det inflammatoriske respons menes via en TNF-alfa-medieret reaktion at kunne øge den splankniske ekspression af NOS og via splanknisk vasodilatation at kunne dearrangere hæmodynamikken.

(Man mener, at inflammationen medfører, at der sker en overproduktion af signal molekylet nitrogen oxid. Det medfører, at der er blodkar der udvider sig, og det forstyrrer det normale flow af blodet.)

Og videre står der om antibiotika behandlingen af patienter med cirrose:

Som anført er translokationen af bakterielle produkter fra især den gramnegative tarmflora hyppigt forekommende, selv hos patienter, der ikke forekommer klinisk inficerede. Som konsekvens heraf har man forsøgt at give cirrotikere bredspektret antibiotikabehandling fra quinolon- og rifamycingruppen. Formålet med dette har været at reducere translokationen af bakterielle produkter fra den gramnegative tarmflora i håb om at kunne bedre hæmodynamikken og beskytte mod komplikationer i forbindelse med cirrose.

Det er pudsigt, at ME/CFS forskeren Julia Newton har sammenlignet primær biliær cirrose med ME/CFS. Det kan man læse om på Cort Johsons blog: Newton’s Apples: Exploring the Ellis Interview with Dr. Julia Newton on Chronic Fatigue Syndrome