When the 'Holiday Season' Is No Holiday at all for Those With ME/CFS
Is December getting to you? Jody Smith shares some thoughts on some of the struggles that all too often attend this time of year ...
Discuss the article on the Forums.

Jarred Younger on Neuroinflammation in ME/CFS and Fibromyalgia

Discussion in 'Latest ME/CFS Research' started by zzz, Jul 15, 2015.

  1. Sushi

    Sushi Moderation Resource Albuquerque

    Messages:
    15,414
    Likes:
    23,797
    Albuquerque
    @Hip Any idea?
     
  2. Hip

    Hip Senior Member

    Messages:
    10,513
    Likes:
    17,220
    This study, which examined the ability of three tetracycline antibiotics (namely minocycline, doxycycline and tetracycline) to inhibit microglial activation during ischemia, used doses of 90 mg per kg of body weight in the animals, which are very high doses. That would correspond to a 7,200 mg dose in an 80 kg human. Normal doses of doxycycline and minocycline are around 200 mg daily. Though the authors did say that "we have also found that significantly lower doses of the compounds are neuroprotective in both global and focal brain ischemia."

    Note that tetracycline antibiotics are not the only microglial activation inhibitors. I complied a list of dozens of microglial activation inhibitors in this thread:

    Chronic Microglial Activation in ME/CFS, And Its Possible Treatment Using Microglial Inhibitors
     
    Last edited: Jul 16, 2015
    leokitten, Thinktank, rosie26 and 4 others like this.
  3. nandixon

    nandixon Senior Member

    Messages:
    846
    Likes:
    2,118
    @Hip, you would probably want to incorporate a body surface area (BSA) conversion factor into the drug dosage calculation. See, e.g.:

    Dose translation from animal to human studies revisited

    So, as a guess for a gerbil to human BSA conversion, you might need to divide that 7200mg amount by about 9, giving a somewhat more reasonable 800mg.
     
    Hip and adreno like this.
  4. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    So far there is no consistent evidence on B cell defects in ME. We are only going on the basis of the apparent benefit from rituximab.

    In autoimmunity the production of bad B cells does not seem to be downstream of anything except itself. There are genetic risk factors but lots of people healthy their whole lives have these risk factors. The production of the bad B cells is a random event like in cancer. There is nothing upstream of the random generation of a particular cancer clone, except again background risk factors that anyone can have.

    It is possible that in some cases there are addressable upstream factors for B cell misbehaviour but I am not sure what they could be.
     
    leokitten, adreno, Valentijn and 2 others like this.
  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    glucocorticoids can produce some benefit in almost any situation so it is a bit hard to know what to make of a response. They have so many different actions.
     
    JamBob likes this.
  6. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    I agree. There are masses of unknowns - at least to me. I think all one could say would be that if a microglial activation inhibitor of some sort produced rapid symptom relief and scans improved but that things relapsed after stopping it might be logical to make use of the microglial drug while waiting for rituximab to have a longer term effect.
     
    Valentijn, Sasha and user9876 like this.
  7. JPV

    JPV ɹǝqɯǝɯ ɹoıuǝs

    Messages:
    858
    Likes:
    1,097
    Thanks for the response.

    Is it possible that the B cells could become dysfunctional after constantly dealing with some type of chronic infection(s)?
     
  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    Not that I can think of. The only dysfunction that would seem t matter is making an antibody against self or at least an antibody that causes problems. That is determined entirely by random mutation within the B cell itself. It cannot be made to happen by an infection or other outside influence.
     
    Valentijn and JPV like this.
  9. Hutan

    Hutan Senior Member

    Messages:
    1,069
    Likes:
    6,437
    New Zealand
    I'm learning about IL10 at the moment, so suddenly IL10 seems part of the answer to most of the questions I'm seeing. Apologies for almost certainly covering old ground.

    The Light et al study found IL10 increases in people with CFS after exercise.
    Perhaps it is possible that IL-10 makes the B cell go rogue? (see the bolded sentences in the reference below)

    And, perhaps it is possible that a pathogen makes the body increase levels of IL-10, makes homologs of IL-10, and/or the body voluntarily increases IL-10 in order to avoid inflammatory damage from a pathogen?


    The Role of IL-10 in Autoimmune Pathology

    Andrew W. Gibson, Jeffrey C. Edberg, Jianming Wu, and Robert P. Kimberly.
    http://www.ncbi.nlm.nih.gov/books/NBK6234/

    High serum levels of IL-10 have been documented in human autoimmune diseases.

    Interleukin-10 is produced by CD4 and CD8T cells, activated B lymphocytes, monocytes, macrophages, and keratinocytes.1,2 As an anti inflammatory cytokine IL-10 down-regulates the expression of Th1 cytokines, MHC class II and costimulatory molecules on macrophages. However, IL-10 also stimulates FcγR expression on the same cells,1,2 and has been shown to prolong B cell survival, to induce B cell differentiation, and to enhance B cell proliferation and antibody production.1-5 The effects of IL-10 on B cells, particularly on the stimulation and survival of autoreactive B cells are believed to be of great importance in autoimmune diseases. 2,5 Additionally, IL-10 may play an important role in influencing the balance of Th1 versus Th2 cytokines, which can influence the progression of autoimmune diseases.6-8


    Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease
    Shankar Subramanian Iyer1 and Genhong Cheng2,*
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410706/

    ...certain pathogens can promote a favorable environment for infection and persistence by expressing IL-10 homologs that bind the IL-10 receptor and exert immunological effects similar to that of the endogenous ligand. This is best characterized in the Epstein-Barr virus encoded IL-10 mimic, BCRF1

    ...several pathogens have evolved mechanisms that selectively up-regulate IL-10 during the course of an infection, presumably to create a more favorable microenvironment. For example, Toxoplasma gondii is capable of shutting down TLR4-mediated LPS signaling in a manner that specifically blocks TNFα expression but allows for production of IL-10

    IL-10 functions as a potent B cell stimulator that enhances activation, proliferation, and differentiation of B cells. This relates to SLE <lupus>, which is characterized by high autoantibody production and decreased cellular immune responses. In SLE, high levels of autoantibodies generate immune complexes that exacerbate tissue damage. Compared with healthy individuals, levels of IL-10 in SLE patients are significantly higher and there is a correlation between IL-10 levels and clinical manifestation.77 Depletion of IL-10 by anti-IL-10 antibody in vitro treatment of SLE patient–derived PBMC significantly decreased autoantibody production.

    And if IL-10 is indeed part of the problem, what makes that disregulated? I have included the following paragraph from this same reference not because I understand it, but it seems to indicate that the regulation of IL-10 production is pretty complicated. Plenty of scope for problems upstream of the B cells I think.

    IL-10 inducing signaling cascades have been studied less thoroughly in 3 cells than in macrophages and DCs. Stimulation of IL-10 expression can occur through one of three mechanisms: (1) instruction by APCs, (2) induction by IL-12 family cytokines, or (3) alternative means << !! >>. T cell receptor (TCR) and endogenous Il-12 have been shown to be essential for the differentiation of IL-10 producing 31 cells as well as for maximal expression of Il-10 following re-stimulation of these cells.106 Il-10 induction in 31 cells is STAT4 and ERK dependent. In 32 cells, Il-10 production appears to be regulated by 32 conditioning factors including IL-4, STAT6 and GATA3. <etc etc>
     
    nandixon and JPV like this.
  10. adreno

    adreno PR activist

    Messages:
    4,841
    Likes:
    11,064
    It was recently discovered that the microbiome has influence on antibody repertoire. I wonder how this might influence autoantibody production?

    http://www.msdiscovery.org/news/new_findings/7379-early-b-cells-found-gut-schooled-microbes
     
    Last edited: Jul 17, 2015
    leokitten, Hutan, Vojta and 1 other person like this.
  11. Sasha

    Sasha Fine, thank you

    Messages:
    12,808
    Likes:
    34,302
    UK
    @Jonathan Edwards, are we talking about an acquired mitochondrial problem in which heritability would play no part? If not, does it make sense to do a PR survey on which family members have ME, like the one you did on thyroid issues?
     
    leokitten, Hutan and girlinthesnow like this.
  12. Bob

    Bob

    Messages:
    10,703
    Likes:
    34,252
    England (south coast)
    Such a survey would be skewed towards mothers because more women than men have ME. But it might be interesting anyway.
     
    Sasha likes this.
  13. Sasha

    Sasha Fine, thank you

    Messages:
    12,808
    Likes:
    34,302
    UK
    That's a good point...
     
  14. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,235
    Likes:
    4,581
    Could autoimmunity be due malfunction from other immune cells, which does maintenance-work on the B-cells? (and is this only T-cells?) A norwegian immunological researcher explained to me that autoimmunity may be caused by malfunction of such regulatory processes on "bad B-cells".. I thought that sounded plausible.. That would implicate that the b-cells aren't necessarily doing anything wrong, however the control that is supposed to find place during e.g the different maturation stages of the b-cells is potentially inadequate.

    I apologize in advance, if i have misunderstood something basic here.
     
    leokitten likes this.
  15. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    You would be in good company! In a sense the issue is basic but the context is so complicated that it is quite difficult to see the wood for the trees. Everyone in immunology is obsessed with the idea that B cells are innocent and just make mistakes because of some other cells like T cells or Tregs. But the mistakes we find in autoimmunity arise from random mutation in the B cells. Other cells might help such bad B cells survive but then you have to give a reason for those cells misbehaving that would specifically help bad B cells. The old molecular mimicry idea simply makes no sense if you look at it carefully. So although it is easy to find hundreds of reviews saying there are upstream mechanisms involving IL-10 or T cell subsets or whatever, nobody actually has a thoery based on that which would generate the specific sorts of bad B cell we find. On the other hand it is quite easy to see how these particular bad B cells might encourage their own survival by producing antibody that fed signals back onto their sisters.
     
    leokitten, Hutan, Scarecrow and 2 others like this.
  16. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,235
    Likes:
    4,581
    Hah! I see. Such upstream-processes must be really hard to research as well i assume?

    Would you be able to illuminate your interesting idea in your last sentence some more? What kind of signals e.g?
     
  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

    Messages:
    5,255
    Likes:
    32,048
    The self-perpetuating signals are various and complicated and not very easy to explain in an internet post. The general idea and several examples were given in a paper I wrote with G Cambridge and V Abrahams in 1999. You shuld find it at
    http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2567.1999.00772.x/full
     
    leokitten and Marky90 like this.
  18. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

    Messages:
    1,235
    Likes:
    4,581
    I imagined! Thanks!
     
  19. FancyMyBlood

    FancyMyBlood Senior Member

    Messages:
    189
    Likes:
    97
    It's much less actually. When translating an animal dose to a human equivalent dose (HED), you need to take into account the animal's body surface area. The entire HED formula is explained here:http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdT

    The study used gerbils and I'm not sure of their BSA, but if it used mice the HED would translate to 90 x 0.081= 7.2 mg/kg. Obviously this formula is just a starting point and the accuracy depends on a lot of factors. Still, it's at least double the generally prescribed doses of minocycline.

    Edit: Just noticed @nandixon already explained it earlier.
     
    leokitten likes this.
  20. Hip

    Hip Senior Member

    Messages:
    10,513
    Likes:
    17,220
    Thanks for pointing that out. I never realized this. Very interesting.

    I have often seen body surface area being used in dose calculations, especially for chemotherapy dosing, but was always puzzled why they used this rather than body volume (which in animals is more or less proportional to body mass, since most animals have similar density) .

    But from reading the papers you guys provided, it seems you must also take other metabolic "processing speed" factors like an animal's metabolic rate, oxygen utilization, energy expenditure and renal function into consideration in order to determine the drug correct dose (and the paper said these factors correlate quite well to body surface area, which is why you use surface area as a rule of thumb measurement).

    Taking an animal's metabolic "processing speed" into account makes sense when you think about it: an animal like a rat has a high overall metabolic processing speed compared to a human, and so this extra speed will be using up and excreting a drug at a higher rate than a human. Thus small animals like rats will require either higher per kg doses of the drug, or more frequent dosing, to keep up with their metabolic speed.

    In that FDA document on page 7 there is a very useful conversion table between various animal mg/kg doses, and human mg/kgdoses.



    Conversion Between Micromolar (μM) Concentrations In Vitro, and a Human Oral Dose

    The other type of dose conversion always I wanted more info on, but could never find any, is the conversion between micromolar (μM) concentrations — which are usually used to express the concentration of a drug in solution applied in cell line experiments in vitro — and the equivalent human oral dose of that drug that would achieve the same level of drug concentration in human tissues.

    Sometimes you read one of these in vitro studies, and you want to try the same drug or supplement yourself, but need to convert from micromole concentrations to an oral dosage in grams.

    I came up with my own formula for this, which is based on the assumption that a normal weight person will have around 40 liters of "accessible" water in their body, and that the drug will distribute in this 40 liters. On that assumption, the conversion formula from micromolar (μM) concentrations to an oral dose in milligrams grams would be:

    Formula for when the concentration C of the solution in vitro is expressed in μM (micromoles per liter = μmol/L):
    Where:
    C = concentration of the solution in μM, used in the in vitro study
    B = percentage bioavailability
    P = percentage plasma protein binding
    W = the molecular weight of the drug or compound in grams per mole

    Or:
    Formula for when the concentration C of the solution in vitro is expressed in μg/ml (micrograms per ml):
    Where:
    C = concentration of the solution in μg/ml, used in the in vitro study
    B = percentage bioavailability
    P = percentage plasma protein binding


    The plasma protein binding percentage P specifies what percentage of the supplement or drug binds to the proteins in the blood. You can find the plasma protein binding percentage of many drugs by searching Google. This percentage can be anything from 0% to 100%. Only the unbound (free) drug is active in the body (usually); the drug bound to plasma proteins becomes inactive; thus the above formula takes this into account, factoring P into the equation.


    Just how valid these formulas are, I am not sure. I expect they will at least provide a rough guide.

    In this discussion they say that there is no easy way to reliably convert from in vitro micromolar concentrations to an oral dose in grams, because too many factors are at play which affect the final concentration that an oral dose achieves. However, I think the formula I devised probably works for getting a rough ballpark figure for the oral dose.



    Note that:

    A molar (M) solution is 1 mole of the chemical dissolved in 1 liter = 1 mol/L
    A millimolar (mM) solution is 1 thousandth of a mole dissolved in 1 liter = 1 mmol/L
    A micromolar (μM) solution is 1 millionth of a mole dissolved in 1 liter = 1 μmol/L
     
    Last edited: May 3, 2018
    olegsel likes this.

See more popular forum discussions.

Share This Page