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Autoantibody pain without inflammation - Review

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Autoantibody pain.
Goebel A.
Autoimmun Rev. 2016.
doi: 10.1016/j.autrev.2016.02.011.
http://www.sciencedirect.com/science/article/pii/S1568997216300374
http://www.ncbi.nlm.nih.gov/pubmed/26883460

Abstract
As autoantibodies bind to target tissues, Fc-region dependent inflammation can induce pain via mediators exciting nociceptors. But recently another possibility has emerged, where autoantibody binding to nociceptors can directly cause pain, without inflammation. This is thought to occur as a result of Fab-region mediated modification of nerve transduction, transmission, or neuropeptide release. In three conditions, complex regional pain syndrome, anti-voltage gated potassium channel complex autoimmunity, and chronic fatigue syndrome, all associated with no or only little inflammation, initial laboratory-, and trial-results have suggested a potential role for autoantibody-mediated mechanisms. More research assessing the pathogenic roles of autoantibodies in these and other chronic pain conditions is required. The concept of autoantibody-mediated pain offers hope for the development of novel therapies for currently intractable pains.
 
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Jonathan Edwards

"Gibberish"
Messages
5,256

lansbergen

Senior Member
Messages
2,512
If it is antibodies then please explain why I improved with a med that does not direct act on Bcells.
 
Messages
5,238
Location
Sofa, UK
...and chronic fatigue syndrome, all associated with no or only little inflammation....
@Jonathan Edwards - is that fair to say? I thought there was plenty of evidence of elevated levels of inflammatory cytokines in ME/CFS, even if the overall picture on that is still rather confused (perhaps partly due to seasonal fluctuations in cytokines which have only recently been recognised).
 
Messages
15,786
Interesting theory and discussion, but I think the author is making a bit of a stretch to make pain a particularly prominent part of ME/CFS. He's also tying it in with central sensitization, and biopsychosocial factors:
Since pain is a ‘biopsychosocial’ condition [61], the contribution of psychological and social factors will also require further study. One wonders whether it is possible that in some instances the brain, perhaps in response to distressing experiences can contribute towards activating the B-cell response.
 
Messages
58
@Jonathan Edwards - is that fair to say? I thought there was plenty of evidence of elevated levels of inflammatory cytokines in ME/CFS, even if the overall picture on that is still rather confused (perhaps partly due to seasonal fluctuations in cytokines which have only recently been recognised).

I believe in this case they mean a lack of swelling and heat in the affected areas, rather than a lack of inflammatory mechanism activation. This is part of the issue with diagnosis, as these physical indicators are missing in CFS/ME and fibromyalgia, but present in other disorders like rheumatoid arthritis.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards - is that fair to say? I thought there was plenty of evidence of elevated levels of inflammatory cytokines in ME/CFS, even if the overall picture on that is still rather confused (perhaps partly due to seasonal fluctuations in cytokines which have only recently been recognised).

The evidence on cytokines is still uncertain. Perhaps the most consistent finding is of raised levels of an 'anti-inflammatory cytokine' TGF beta. And cytokines don't make inflammation. They are a potential causal factor in inflammation but inflammation requires finding increased vascular permeability or cell migration. There are non-inflammatory diseases with high 'inflammatory' cytokine levels. Castleman's disease is one.

I missed the bit about pain being psychosocial. A bit like getting an email saying 'Your Paypall account has been closed', this rather lowers the impression of cogent debate.
 

Hip

Senior Member
Messages
17,824
...and chronic fatigue syndrome, all associated with no or only little inflammation....
is that fair to say?

If I remember rightly (and I probably don't), I think @Butydoc once remarked that the sort of inflammation usually medically signified by the suffix -itis (as conjunctivitis, encephalitis or encephalomyelitis) is not generally found in ME/CFS (in spite of this disease being called myalgic encephalomyelitis).

I think in ME/CFS, the brain inflammation is a little more subtle. The first evidence for neuroinflammation in ME/CFS that I am aware of comes from this Japanese study:

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study
 
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kangaSue

Senior Member
Messages
1,851
Location
Brisbane, Australia
Interesting theory and discussion, but I think the author is making a bit of a stretch to make pain a particularly prominent part of ME/CFS
Voltage-gated potassium channels (VGKC) have received a lot of attention for involvement as one of the pathways in neuropathic and muscular pain. Complex Regional Pain syndrome can be alleviated by the pain med flupirtine which is widely available in Europe or it's closely related sister drug retigabine (an anti-seizure med) through their action as potassium channel activators. I don't think there is any reason to expect that it couldn't be a pain pathway in ME/CFS too.
http://www.ncbi.nlm.nih.gov/pubmed/22895588
http://www.hindawi.com/journals/ecam/2012/803082/


Blockade of VGKC pathway also interferes with other signalling processes too so having antibodies to VGKC has a wider implication than just pain issues and can affect smooth muscle transmission signals to many organs including gastric motility.

Some people with CFS have good general improvement by taking cardiac nitrates which also activate some potassium channels. Whether that's down to VGKC antibodies or just balancing out excess calcium channel release, which does affect those with CFS, is another question..
http://cvpharmacology.com/vasodilator/nitro

There is a commercial test widely available for VGKC antibodies. In Australia it's about $100 through a pathology lab but my G.P. gave me the tip that if you take anyone's pathology request to a public hospital pathology department it will likely be bulk billed and cost you nothing. That was my experience (I don't have CFS, I was looking to see if it was these antibodies affecting my G.I. motility)

 

Hip

Senior Member
Messages
17,824
Voltage-gated potassium channels (VGKC) have received a lot of attention for involvement as one of the pathways in neuropathic and muscular pain.

In coxsackievirus B3 infection of rat myocytes (muscle cells), perturbations to potassium and calcium ion currents was observed in this study, which found that:

CVB3 infection increased:
L-type voltage-dependent calcium channel current
outward potassium current


CVB3 infection decreased:
inwardly rectifying potassium current

CVB3 infection had no obvious effect on:
sodium current


Lots of the early British studies on myalgic encephalomyelitis found coxsackievirus B / enterovirus muscle infections were much more common in ME/CFS patients.

So it seems plausible that such coxsackievirus B infections in the muscles of ME/CFS patients might be triggering pain and/or altered sensation by their effect on ion channels.
 

Deltrus

Senior Member
Messages
271
In coxsackievirus B3 infection of rat myocytes (muscle cells), perturbations to potassium and calcium ion currents was observed in this study, which found that:

CVB3 infection increased:
L-type voltage-dependent calcium channel current
outward potassium current


CVB3 infection decreased:
inwardly rectifying potassium current

CVB3 infection had no obvious effect on:
sodium current


Lots of the early British studies on myalgic encephalomyelitis found coxsackievirus B / enterovirus muscle infections were much more common in ME/CFS patients.

So it seems plausible that such coxsackievirus B infections in the muscles of ME/CFS patients might be triggering pain and/or altered sensation by their effect on ion channels.

Thanks for this! I was just looking for the effect of coxsackie b virus on ion channels yesterday. Phenibut pretty much cures me and blocks a subunit of voltage gated calcium channels. My fatigue started with reoccurring pericarditis, and now I have pain along my vagus nerve. I have symptoms of muscle tension, nerve pain mainly along the vagus nerve on the right side, fatigue, and gastroparesis.

This thread makes me really interested in the drug @kangaSue mentions too. But first I'm trying oxymatrine.

My theory is that the ion imbalance in the vagus nerve is causing acetylcholine release which lowers local inflammation. At the same time, the ion imbalance disrupts signalling.

My fatigue gets worse when I'm driving long distance or doing mild work in the heat. It gets worse with boring activity. I think it's because of the lack of anti-inflammatory activity of dopamine along with viral reactivation.

EDIT: Actually it seems like coxsackie b causes potassium to EXIT the cell which would normally decrease excitation. This is similar to potassium deficiency which would normally DECREASE extracellular potassium which would enhance the excretion of potassium ions from cells. However instead of making muscles relaxed, potassium deficiency causes muscle twitches and contraction because the cells need certain ion concentrations to maintain their mechanisms.
 
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Hip

Senior Member
Messages
17,824
Thanks for this! I was just looking for the effect of coxsackie b virus on ion channels yesterday.

Well there is a coincidence!

A few years ago, I was wondering whether the effects of CVB on intracellular potassium might be causing some of the symptoms of ME/CFS. From what I can see from that study, the effects would be to reduce overall intracellular potassium, because of the increased outward potassium current, and decreased inwardly rectifying potassium channel current caused by CVB in that study. (Note that inwardly rectifying potassium channels allow potassium to move more easily into the cell, and less easily out of the cell, so their overall effect I think is to move potassium into the cell).

Intracellular potassium (along with intracellular magnesium) has been speculated to be low in many ME/CFS patients anyway, so this data from CVB infection falls in line with this.

I was trying to come up with some interventions that might counter the effects of CVB on potassium channels, in order to raise intracellular potassium.

I did not really have much success, but found the following info:

Luteinizing hormone inhibits potassium outward currents.

Cannabinoids activate an inwardly rectifying potassium conductance. Ref: 1

Pregnenolone sulfate potentiates the inwardly rectifying K channel Kir2.3. Ref: 1
 

Deltrus

Senior Member
Messages
271
@Hip I respond well personally to phenibut and diphenhydramine. If you look on the table here: https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor#Difference_in_G_proteins

you can see that activation of the m2 and m4 receptor causes an increase in potassium conductance and a decrease in calcium conductance.

That means that inhibiting these receptors would decrease potassium conductance(theoretically good) and increase calcium conductance(theoretically bad).



https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M2
M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors.[8]

In addition, they modulate muscarinic potassium channels.[9][10] In the heart, this contributes to a decreased heart rate. They do so by the G beta gamma subunit of the G protein coupled to M2. This part of the G protein can open K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium, which slows down the heart rate.

According to this: https://en.wikipedia.org/wiki/Heterotrimeric_G_protein
Gq is attached to m1, m3, and m5 receptors, and it increases intracellular calcium. So the end result of diphenhydramine blocking the m1-5 receptors would be a increase in increased cellular potassium and decreased intracellular calcium.

Potentially, the parasympathetic nervous system has issues because normally it has lower potassium and higher calcium because of these receptors, and then coxsackie virus further increased calcium and lowers potassium.

I previously had GREAT success stacking 500 mg phenibut with 50 mg dipihenhydramine. The result of the stack was like normal phenibut, removal of fatigue, much improved digestion etc, but I had to use much less phenibut for a good result. In addition, I got much more locomotion and physical energy than I would have with phenibut. I had an urge to move around rather than sitting in my room. With phenibut alone in higher doses, I would only be sitting still studying or playing video games without fatigue.

Sadly apparently anti-histamines that cross the blood brain barrier cause a downregulation of glutamine synthesis in astrocytes, which leads to less glutamate uptake, and reduced presynaptic glutamate/gaba. The result is that gaba lowers, while synaptic glutamate stays the same, increasing chance of seizures. I took diphenhydramine for 4 days and got this effect fully, which is cool, because now I can say exactly how an increased glutamate/gaba ratio "feels" like.

Also anti-cholinergics cause memory problems and brain fog with sustained use.

The cannabinoid thing is interesting:
An endogenous cannabinoid, anandamide, activated Kir and inhibited ICa as efficaciously as potent cannabinoid agonist.

I have the gene which lowers FAAH which degrades anandamide. It is called the "bliss" gene. I can say that when I'm experiencing bliss, normally when I read an extremely good book and drinking coffee at the same time, I feel some of the best relief to my chronic fatigue.
 
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Hip

Senior Member
Messages
17,824
you can see that activation of the m2 and m4 receptor causes an increase in potassium conductance and a decrease in calcium conductance.

That means that inhibiting these receptors would decrease potassium conductance(theoretically good) and increase calcium conductance(theoretically bad).

I could be wrong, but I don't think conductance tells you which way the K+ ion flows (ie, in or out of the cell); it just tells you about the rate of flow through the various potassium ion channels. Increased conductance implies an increased rate of flow of K+ ions, but whether that flow is in the inwards or outwards direction is another matter.
 

roller

wiggle jiggle
Messages
775
my c-reactiv prot was low, my blood potassium ok, urine kalium + calcium ok.
my pain comes and go and switches from one body half to the other, and may be at both sides as well. e.g. hips, since puberty regular.

abx help always, the weakest however doxy, and after some time doxy it comes back.
glucosamine/msm/chondroitin seemed zero effect.

recently i came across bursitis.
im wondering, if them may be able to build up in such a short time (overnight)?
they may be filled with bacteria..

they cause calcium deposits, but not necessarily high calcium in the blood, which may go in fact deficient after some time.

perhaps they are build when the body was unable to remove toxins overnight?
 
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Deltrus

Senior Member
Messages
271
I could be wrong, but I don't think conductance tells you which way the K+ ion flows (ie, in or out of the cell); it just tells you about the rate of flow through the various potassium ion channels. Increased conductance implies an increased rate of flow of K+ ions, but whether that flow is in the inwards or outwards direction is another matter.

Yeah I was a bit confused as well, I think you are right. I didn't read this part properly:

"They do so by the G beta gamma subunit of the G protein coupled to M2. This part of the G protein can open K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium".

I thought it was mediated by the Gi protein now the beta gamma subunit. Geez these secondary messanger G protein things are confusing.

https://en.wikipedia.org/wiki/Heterotrimeric_G_protein says the Gi protein:
opens K+-channels (via β/γ subunits)

https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M2
They do so by the G beta gamma subunit of the G protein coupled to M2. This part of the G protein can open K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium

So apparently the β/γ subunit opening causes an outward current in the heart. Hard to tell if it causes an outward current everywhere.

This system's complexity is over my head I think.
 
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