Lipkin's Monster ME/CFS Study: Microbes, Immunity & Big Data
The Microbe Discovery Project outlines an ambitious new study by top researchers that has collected patient samples, but needs desperately funds to complete the work.
Discuss the article on the Forums.

Autoantibody pain without inflammation - Review

Discussion in 'Latest ME/CFS Research' started by Bob, Feb 18, 2016.

  1. Bob

    Bob

    Messages:
    10,703
    Likes:
    34,252
    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

     
    Last edited: Feb 18, 2016
    Valentijn and Gemini like this.
  2. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,046
    Snow Leopard, Kati and Bob like this.
  3. A.B.

    A.B. Senior Member

    Messages:
    3,750
    Likes:
    23,204
    Full paper here:

    http://www.ncbi.nlm.nih.gov.sci-hub.io/pubmed/26883460#
     
    Valentijn likes this.
  4. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,046
    Cheshire, MEMum, Valentijn and 2 others like this.
  5. lansbergen

    lansbergen Senior Member

    Messages:
    2,511
    Likes:
    2,726
    If it is antibodies then please explain why I improved with a med that does not direct act on Bcells.
     
  6. Mark

    Mark Former CEO

    Messages:
    5,224
    Likes:
    6,199
    Sofa, UK
    @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).
     
    Valentijn and msf like this.
  7. Valentijn

    Valentijn Senior Member

    Messages:
    14,281
    Likes:
    45,876
    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:
     
    Cheshire, MEMum and ScottTriGuy like this.
  8. Marco

    Marco Grrrrrrr!

    Messages:
    2,380
    Likes:
    3,200
    Near Cognac, France
    Has anyone ever tried passive transfer of IgG from ME/CFS patients to animals and would a failure to produce symptoms be definitive?
     
  9. sdmcvicar

    sdmcvicar

    Messages:
    58
    Likes:
    240
    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.
     
    A.B. and Valentijn like this.
  10. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,046
    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.
     
    Valentijn and Kati like this.
  11. Hip

    Hip Senior Member

    Messages:
    10,477
    Likes:
    17,165
    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
     
    Last edited: Feb 19, 2016
    Kati likes this.
  12. kangaSue

    kangaSue Senior Member

    Messages:
    949
    Likes:
    1,069
    Brisbane, Australia
    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)

     
    Deltrus likes this.
  13. Hip

    Hip Senior Member

    Messages:
    10,477
    Likes:
    17,165
    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 likes this.
  14. Deltrus

    Deltrus Senior Member

    Messages:
    271
    Likes:
    359
    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.
     
    Last edited: Feb 26, 2016
  15. Hip

    Hip Senior Member

    Messages:
    10,477
    Likes:
    17,165
    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
     
  16. Deltrus

    Deltrus Senior Member

    Messages:
    271
    Likes:
    359
    @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
    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:
    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.
     
    Last edited: Feb 26, 2016
  17. Hip

    Hip Senior Member

    Messages:
    10,477
    Likes:
    17,165
    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.
     
  18. roller

    roller wiggle jiggle

    Messages:
    451
    Likes:
    218
    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?
     
    Last edited: Feb 26, 2016
  19. Deltrus

    Deltrus Senior Member

    Messages:
    271
    Likes:
    359
    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:
    https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M2
    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.
     
    Last edited: Feb 26, 2016

See more popular forum discussions.

Share This Page