Monday, 24 June 2013

Concept for Relapsing disease orderly epitope spread should be Dead

As an editor I have the capacity to modify Posts 

YOU HAVE BEEN DIRECTED TO THIS PAGE BY SOMEONE WHO THINKS THEY ARE BEING CLEVER...EM 

EpubWegmann et al. Targeting T cells responsive to the priming epitope prevent the relapsing phase of experimental autoimmune encephalomyelitis.  J Neuroimmunol. 2013 Jul 15;260(1-2):74-81.

Upon recovery from the initial episode of experimental autoimmune encephalomyelitis (EAE), virtually all SJL mice develop relapsing/remitting episodes of disease. These relapses may occur due to the reactivation of memory T cells initially stimulated as part of the disease-inducing protocol or naïve T-cell populations stimulated by distinct encephalitogens derived from the inflammatory disease process (epitope spread). We have used encephalitogen-specific non-linear peptide octamers to modify the course of relapsing EAE (rEAE) in SJL mice immunized with an oliogodendrocyte-specific protein peptide (OSP 55-71). Our studies show that the peptide-octamers, which target the T cells stimulated by the priming encephalitogen, but not other candidate encephalitogens, prevent rEAE.




How does an infection lead to autoimmunity...along came the concept of epitope spread whereby damage resulting from viral infection lead to the the development of autoimmunity. This is a nice concept and could explain relapsing disease or how MS could develop and there is no question in my mind that immune reactivity to self targets increase as time goes by...but here is the problem when it is taken to extreme. There are some parts of the science fraternity who believe that relapses are the result of epitope spreading from one epitope to another in an orderly fashion. 

About two minutes of thought should tell you that this is probably a rubbish, concept especially as there are hundreds of lesional events (10 or more per relapse) and the important fact that no-one bar a few labs can replicate this ordered response. This new paper is yet another example how one dubious idea can take many many publications to try and break the idea.  

How  would relapses in T cell receptor transgenic mice occur when they only react to one specificity. Need we say more? 

MD2 will point out that we showed that this concept was on shady ground about 8-10 years ago.

6 comments:

  1. Interesting that this paper is in J Neuroimmunol as is our old paper (2005) showing the same thing rather than in the high impact journals that the original studies were published and that these findings contradict. Seems to me that there is an overt/covert attempt to try and reduce the impact of these findings but maybe that's me being even more paranoid than I already am!
    http://www.ncbi.nlm.nih.gov/pubmed/15927270

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  2. I thought this debate was already solved?

    http://www.ncbi.nlm.nih.gov/pubmed/20826011

    So if a pathogen does not initiate relapse, what is your best guess as a cause?

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  3. This seems to support the study by Miller' group that tolerance can be restored using a fixed number of primary epitopes. Where do B-cells come into play? Besides clonal B-cells producing antibody do they also behave like T-cells?

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    1. Yes possibly, as we showed many years ago, if you get immune tolerance to dominant epitope in long established disease that drives the process then you have a chance of stopping the process even though there are responses to other minor epitopes. This is why the original dogma, of relapses going from one epitope to the next was seriously flawed.

      So the idea created by the group would mean that you had to know where in the attack process you were for this approach of a fixed number of peptides to work. Maybe the leopard changes its spots.

      As MD2 says the "weight of evidence is certainly building up against the original dogma but whether the sheep will accept this is another matter!"

      Where do B-cells come into play? Besides clonal B-cells producing antibody do they also behave like T-cells?

      Simple answer is they don't...this approach is geared towards T cells and now depending on the which year you started to read the dogma will depend on what the result is.

      (a) If you remove T cell help you do notgetan antibody response
      (b) If creates a shift from Th1 (autoimmune cells) to Th2 cells (Th1 regulatory cells but allergy antibody producing cells)
      (c) It creates split tolerance, it reduces T cell responses and increases B cell responses....but this depends on the amount of antigen given and a high doses can inhibit antibody formation
      (d) It produce IgE anaphylactic myelin-specific antibody
      (e) It produces IgG myelin-specific antibodies that augment immunity

      It is a known fact that when trying to make monoclonal antibodies that you give an intravenous boost before doing this and so it can drive antibody responses.

      As to what occurs in humans we will find out when this approach was used with myelin basic protein it was claimed that antibodies were reduced suggesting that (a) was occurring....let's hope this is the case because if not one of prof G study will not work and the Miller/Martin study you refer to will have problems.

      We know that intravenous myelin basic protein is not the answer for SPMSers as this approach was tried and as we predicted failed, because we currently do believe that SPMS is not driven by T cell autoimmunity...the vast majority of experimental neuroimmunologists cling to that view.

      How do you convince them otherwise, there is always an escape clause, as they just say the immune response is now comartmentalized and has moved into the brain so the drugs do not touch them so it is still all T cell driven. Is one T cell enough? Is it the B cell follicles are they driven by T cells.

      Does cyclosphosphamide(gets in the brain) stop progression,but does it kill T cells...they do not need to divide to do their job as so maybe no. Fingolimod gets in the brain but the mechanism of action is to stop cells getting in the brain as so this immune action does not need to be in the brain. It does not work better in relapsing disease than antibodies that would be predicted to be excluded from the brain.

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    2. Maybe the leopard changes its spots....

      For what you are saying maybe it is the "rat jumping from a sinking ship" :-)

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    3. The nature of science is to change your mind when the hypothesis fails but it is always easier if you can sink your own failed ideas rather having loads of studies showing the original study was not quite right.

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