Thursday, 13 March 2014

EBV re-activation in relapses

Is the black swan circling in already? Is ocrelizumab the game-changer? #MSBlog #MSReseach

Peripheral blood EBV reaction appears to be linked to relapses. Has Michael Pender being focusing on the wrong compartment? #MSBlog #MSResearch

"The study below is a difficult one to interpret and it is small. The researchers took blood from MSers in remission and relapse and compared them to healthy control subjects. They used a technique to look at the type of genes that are active in white blood cells; this is called transcriptomics. A transcript refers to piece of RNA that is used by the cell to make a protein. They showed a difference between remission and relapse (I am not surprised) and a difference between males and females. Why? The results are also affected by many of the MSers being on treatment. It is interesting that their data supports EBV reactivation in relapse. There are data supporting this observation from other studies. EBV reactivation could be a non-specific association or it could potentially be driving relapses. The only way to sort this out is to test an anti-EBV drug in MS. We have been trying to make a case for an EBV anti-viral trial for some years, but the peer reviewers were not supportive. May be it is time for us to relook at this?"

"Anti-CD20 therapies Ocrelizumab and Ofatumumab that target B cells by depeleting them, are also anti-EBV drugs, and are providing very promising early results. These two drugs are the potential game changers in the field. It is important to find out if they are working via targeting EBV. I have stated many times that many of the current DMTs have a sell-by date on them; not long after ocrelizumab is launched. May be the black swan I have been referring to is already circling and waiting to land?"


Functional relations between some of the genes of the male module and processes, cells and events known to be involved in multiple sclerosis as described by literature. Figure is from PLoS One 2014; 28:9(2):e90482.
  
Irizar et al. Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression. PLoS One. 2014 Feb 28;9(2):e90482.

BACKGROUND: Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMSers.


RESULTS: The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 MSers in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called "mirror pattern": they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules.

CONCLUSIONS: The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the "primed" state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS.

CoI: multiple

8 comments:

  1. I don't really understand it, but I like that you're excited by the study. I think it's saying that EBV reactivation causes relapses. Would it go so far as to suggest that MS is a different disease in men than it is in women? And does it give us any further leads on the autoimmunity/neurodegeneration question?

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  2. Prof G,

    If you have time:

    Any thoughts on what anti-ebv agent will be most effective e.g. B cell depleting treatments, Prof Pender's approach, or the treatment being trialled by the Charcot Project?

    When can we expect to see results fro Ocrelezumab phase 3 trials? I think Biogen are the company behind this drug. If it is really effective, won't this impact on all their other MS therapies?

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  3. Lots of questions-

    1. What is the reference to vitamin B12 in the conclusions?

    2. Please explain the remark about Michael Pender and the wrong compartment

    3. Patients on ocrelizumab etc will probably have no new lesions. As with natalizumab, alemtuzumab, etc it will be a long wait before we know about slow progression and SPMS. But what is your best guess: is there any reason to believe that anti-CD20 therapies will do more to prevent or reduce progression?

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  4. Very interesting article prof G.
    we can only hope Anti-CD20 therapies will be available soon


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  5. If EBV is the driver of MS and PPMS is the same disease, why is it that B cell depletion fails in MS?
    BTW is anyone in the Ocrelizumab PPMS trial seeing any results?

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    1. If the therapies don't work in PPMS how will they prevent progression in RRMSers?

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  6. Come on Prof,
    Is anyone with PPMS, in the Ocrelizumab trial seeing positive results?
    Would you put your money on this stuff or what Michael Pender is doing?
    I think I would choose Pender,not least because he has the decency to reply when he is emailed!

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    Replies
    1. It will not be a simple answer based on rituximab study the gadolinium enhancing people wilo benefit i a m not sure the non gadolinium enhancing msers will but we have to wait for the results

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