Blog Essay: Mouse EAE is a T -cell disease….Discuss

B

It is exam times at university and if I was setting an exam for the London School of EAEers, this is the title I would give. OK it is supposed to be contentious. Maybe it is time to retire as that Mr Hyde keeps popping up

As a card carrying EAEer I think I can comment on this one presented by NDG today and hope that it my constructive comments will get me into trouble with the EAE trade Union. NDG has spotted a good paper to discuss and the conclusion is that anti-CD20 that depletes B cells in the periphery, but does not get rid of CNS infiltrates. They also show that CD20 depletion does not inhibit EAE. So it replicates the human experiment that has been done quite a few times?…..anti CD20 does not get rid of oligoclonal bands….at least not quickly. I guess we forget that antiCD20 does not inhibit EAE!

This is Popperian science done backwards. The basis of this is that Karl Popper suggests that you can never prove a hypothesis but you can disprove it and therefore the experiements should be designed to show you ideas are wrong. Sadly this seems to be a thing of the past and experiments large focus on supporting ideas but funnily in the urge to explain what is going on in MS they are doing abit of Popperian science for me.

This is yet further support for a major Hypothesises on mine:

Yep. EAE is a T cell-mediated condition

This study does not disprove the hypothesis so we can come back for another day to do the same. However, it is not going to be me doing these experiments. We saw the light years ago and concluded that CD20-depletion is largely irrelevant to mouse EAE…so there is a fundemental difference, so why work with mice to do this…So we don’t

Sefia E, Pryce G, Meier UC, Giovannoni G, Baker D. Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. Mult Scler Relat Disord. 2017 May;14:46-50.

If the hypothesis is EAE is a B cell mediated problem…..Then the idea has been shot down in flames here and to be honest it has been shot down so many times I am surprised this idea is still flying. If we could only make planes out of this material, air crashes would be a thing of the past.

Here CD20 depletion does essentially nothing. However, we have the MS data so we get Cinderella science where the the shoe must fit…so we will try again. Some people report on positive results for what are only marginal results. that do not pass the smack you in the eye test? But good to see here……..that is a solid it does nothing.

However the main point is that you ask does the model have sufficient validity for human disease because anti-CD20 works in MS it doesn’t in EAE so there is something fundementally different. They get EAE because they have infiltrates in the CNS. The funnisest result is when people forget their own data. People say there is B cell-dependent disease. In my mind this is at best a T cell disease that it has been toned down so much that you need B cells and dendritic cells to get disease. Do they ever deplete T cells in the B cell dependent disease…No because it is T cell dependent and it would block disease.

So EAEers do anti-CD20 in the B cell dependent EAE and the results show CD20 depletion does a little better…Do it in the B cell-independent EAE and its a little worse. Then you realise that they have forgotten their own work that reports that the way they induced the B cell-dependent EAE, it is not B cell dependent, so the results are two poles of the same experiment. Put them together and you get…yep Nothing….CD20 depletion does nothing….So more support for my Hypothesis. Popper science survives for another day.

To be fair in the paper above they say they knew that anti-CD20 would not inhibit disease because it had been done before and it didn’t inhibit disease then either, but a different question was been asked here and says that some infiltrate can survive B cell depletion. What would have happened if T cell depletion has been done? However, we then bring the next hypothesis that antibody does not enter the brain that well…so here they still find some, albeit alot less B cells in the brain. “Studies in human subjects treated with ɑCD20 mAb are required to confirm our results”….Sorry to say they don’t…. CD20 inhibits MS.

Disclaimer: Please note that the opinions expressed here are those of author and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

MouseDoctor

3 comments

  • “CD20 inhibits MS” – but not entirely.

    Unless I’m much mistaken lymphocytes are generated outside the brain / CNS and migrate in there across the blood-brain barrier and attack the spine / brain. So osmosis being what it is – there are going to be B cells heading across there (or not for those of us on anti-CD20 therapies) and there are going to be T cells heading across there (or maybe not for those of us on anti-CD52 therapies) and there are going to be a bunch of other sundry bits and pieces wandering their way across.

    In all likelihood I believe that smouldering MS will turn out to be a broad-spectrum immune attack – the “other” bits of the immune system having been trained by the now-absent B cells. I believe that “curing” MS will probably consist of a number of approaches:

    1.) vaccinating against EBV with one of the new fangled mRNA vaccines – both in the young and in those already with MS.
    2.) somehow training B cells NOT to attack myelin.
    3.) somehow training the rest of the immune system to forget about myelin.
    4.) somehow stimulating nerve and myelin regrowth.

    They’re currently working on #1 and #4. I’m concerned that doing #4 without resetting the immune system to some extent is counter-productive. Hopefully the trials being conducted will take this into account and encourage IRT…

  • I think that even if they were humanized mice they might still be a T cell mediated disease and that boils down to how EAE is initiated in the first place. If I had to make a bet I think EBV invades the central nervous system then age-associated B cells ( ABCs ) go after these infected B cells ( in the cns ) which then causes this ongoing inflammation. With time, T cells get recruited within the cns but the very first thing that gets it started are these age-associated B cells going after ebv infected cells.

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives