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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. lansbergen

    lansbergen Senior Member

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    You are right.
    Still not much progress then.

    I guess there are not many experienced researchers who can interpret the array results.
     
  2. Marco

    Marco Old blackguard

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    I'd be interested to know if you have any thoughts as to how to narrow down the search given that most ME/CFS symptoms are non-specific and multi-system and the one symptom that may be relatively unique (PEM) isn't as yet explained in terms of any specific physiology?

    Secondly (and this may be a daft question) - do you need to identify what antibodies are binding to, to confirm that you are dealing with an autoimmune disease? Presumably repeated successful trials of Rituximab (if that were the case) might point this way but not conclusively?
     
  3. Jonathan Edwards

    Jonathan Edwards Board Member

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    Difficult to say, I think, but receptors on nerve or muscle or more generally for cytokines might be things to go for first I guess.

    If an autoimmune disease is by definition one with adaptive immune reactivity to self, which so far has meant autoantibodies, then it would seem you need to find the antibodies to call it that. You may find the antibodies in a form in which you do not know what they are binding to though. In MS it is still not sure that the antibodies are even against self, although some of them would seem to have to be. For a long time all that was known about autoantibodies was the tissue they bound to, not the antigen. Moreover, we are increasingly finding that autoimmune diseases can have more than one autoantibody and it is not clear which one does what. In RA there are rheumatoid factors and anti-citrullinated protein antibodies and it is not clear how the interrelate.

    Having said all that, if we find a shift in B cell behaviour (maybe a bit like in MS) and a response to rituximab that follows the same sort of kinetics as for autoimmune diseases then I think we have pretty good evidence for an autoimmune mechanism. And knowing what the antibodies are to may not be of any great importance to finding better treatments as time goes by. That is why in some ways I think it may be more useful to find some shift in B cell behaviour rather than a specific antibody, because it might relate more closely to how one might develop therapies.
     
  4. Marco

    Marco Old blackguard

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    Many thanks.

    On the face of it then, that sounds more of a manageable task than looking for the needle in a haystack of possibilities?
     
    ukxmrv likes this.
  5. lansbergen

    lansbergen Senior Member

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    Will that be tested in the trial?
     
  6. Jonathan Edwards

    Jonathan Edwards Board Member

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    I hope so.
     
    aimossy and ukxmrv like this.
  7. lansbergen

    lansbergen Senior Member

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    Then I asume you will advice it. I guess it was not calculated in the cost estimate and more money will be needed.

    Maybe the advocates on here can help raising the money.

    It would be stupid to do a B cell depletion trial and not look for differences between the old B cell actions and the new ones if the tests are availeble.
     
    ukxmrv likes this.
  8. Gemini

    Gemini Senior Member

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    Professor, could you please give a mini-tutorial on what you mean by "shift in B-cell behavior"? I'm wondering if you mean the study of B-cell sub-populations such as that done by Dr. Bansal in ME/CFS or something entirely else?
     
    rosie26 likes this.
  9. ukxmrv

    ukxmrv Senior Member

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    Thanks Professor Edwards for all your valuable contributions here.

    I'm wondering if genetic factors will be found to have any value in determining who will respond to Rituximab? Just looking at a paper here which analysed a interleukin-6 gene polymorphism.

    http://www.ncbi.nlm.nih.gov/pubmed/22734797

    <snip> These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted <end>

    I looked up that gene and it is included in the 23andme report I downloaded.

    The paper from 2012 does have the usual disclaimer that "Validation of these findings in independent cohorts is warranted" so this may not pan out of course given further study.
     
  10. Marco

    Marco Old blackguard

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    Funny you should mention IL6.

    I came across this abstract yesterday (the full paper is pay to view unfortunately) :

    Role of interleukin-6 in stress, sleep, and fatigue

    http://onlinelibrary.wiley.com/doi/...ionid=0A05D9E6672C79C5D5287482A21B960B.d04t04
     
  11. Marco

    Marco Old blackguard

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    Funny you should mention IL6.

    I came across this abstract yesterday (the full paper is pay to view unfortunately) :

    Role of interleukin-6 in stress, sleep, and fatigue

    http://onlinelibrary.wiley.com/doi/...ionid=0A05D9E6672C79C5D5287482A21B960B.d04t04
     
  12. Jonathan Edwards

    Jonathan Edwards Board Member

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    The IL-6 polymorphism link is certainly interesting. I think it would be helpful to repeat the study on homogeneous disease groups like RA or lupus. The effect might turn out to be different for each disease mechanism. Finding such variation in responses in ME is I think a fine detail in comparison to just getting the data confirmed and trying to get an idea who might have B cell related disease and who might not. Interesting though.
     
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  13. Jonathan Edwards

    Jonathan Edwards Board Member

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    Dr Bansal's data would certainly qualify but we might see all sorts of shifts in B cell dynamics. Levels of the B cell growth factor BAFF and its receptors might be interesting as it might tell us the system is in 'overdrive'. There are other markers that might suggest a shift towards tending to make autoantibodies - like the usage of certain heavy chain genes for making antibodies - but it all gets a bit technical from there on (even for me).
     
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  14. Sasha

    Sasha Fine, thank you

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    The interview that Prof. Edwards kindly agreed to is up on the homepage now:

    http://phoenixrising.me/archives/18701

    but I suggest that we bring any discussion back to this thread so it's all in one place.
     
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  15. Gemini

    Gemini Senior Member

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    Professor Edwards, thank you so very much for educating us and keeping us focused. A while back I found this figure in "B cells in HIV infection and disease" by Moir & Fauci showing B cell interactions (drag image down to reposition).The paper concludes with a very short section on autoimmune diseases mentioning rituximab.

    http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click on image to zoom&p=PMC3&id=2779527_nihms156340f2.jpg

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779527/
     
    rosie26 likes this.
  16. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Thank you so much Jonathan Edwards for joining this forum and entering into discussion with us on these complex topics that are so vital to us.

    Forgive me for jumping in and asking a question without having read the whole thread, but here goes!

    Recently Professor Kenny De Meirleir et al published:
    Plasmacytoid Dendritic Cells in the Duodenum of Individuals Diagnosed with Myalgic Encephalomyelitis Are Uniquely Immunoreactive to Antibodies to Human Endogenous Retroviral Proteins


    http://iv.iiarjournals.org/content/27/2/177.full

    And one of the interesting findings was: (from the Abstract)


    These findings are in ongoing investigation but I believe that the autoimmunity that was found cannot be tested by the usual markers. I wonder if this research would be of interest in your current investigation plan?
    Thanks,
    Sushi
     
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  17. wastwater

    wastwater Senior Member

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    I visit and find the Encephalitis society and the St Barts MS blog interesting,not that I understand much,maybe clues can be found in these areas too.
     
    NK17 likes this.
  18. Jonathan Edwards

    Jonathan Edwards Board Member

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    Thanks, that would not be autoimmunity. I think they found that antibodies to viruses (from somewhere else) also bound to duodenal cells from patients. To be honest the abstract does not quite make sense so I am not sure what to think.
     
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  19. lansbergen

    lansbergen Senior Member

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    With from somewere else you mean the retrovirus antibodies they used?

    It falls outside this trial but the question is why do patients pDC's in the duodenum make EVR proteins.
     
  20. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, I guess the antibodies were from some lab reagent raised against the virus. I am not sure you can conclude that the cells were making viral proteins. Dendritic cells pick up antibodies in other ways and the antibody reagent may happen to cross react with some human protein. Cross reactivities are very very common when using lab raised antibodies but I am sceptical about them occurring in real human beings.
     
    Firestormm likes this.

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