Friday, 30 October 2015

There is autoimmunity in MS. B means Bad!

Blauth K, Soltys J, Matschulat A, Reiter CR, Ritchie A, Baird NL, Bennett JL, Owens GP. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol. 2015 Oct 28. [Epub ahead of print]

B cells are implicated in the aetiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.

This study clearly shows what we have been saying....for ever..and that is B cells are bad news.

So it is not surprising that all drugs (bar one) that really work well in MS, block B cell function.

Immunologists have spent years trying to drive a Th1 (Autoimmunity causing) response into a Th2 (antibody/allergy causing) response..that is until Tregs came along :-), which would have made T cells that help B cells to produce antibodies would be bad news. Just as well we did not waste any energy trying to do this. It was always clear to us that both Th1 and Th2 are bad news despite the dogma, get rid of both of them.

In this study they take B cells from the cells in the CNS and manufacture the antibodies that they produce and make some synthetic antibodies. It is clear that some of these respond to brain tissue and so there is autoimmunity in MS

It is equally clear that they are largely not against myelin. So where does this put the idea held by some that mylein basic protein as the main target in MS, but many years ago it was shown that T cell reaction of MBP was a minor thing and when you do react you get peripheral neuropathy.

The antibodies targeted nerves and glia and could easily cause nerve damage and demyelination and this could drive progressive nerve damage and tells us that we need to get rid of plasma cells in the CNS. 

We have to remember that they may not be the real cause but a consequence of events whereby damage caused release of nerve and glial components that caused an antibody response and this is perhaps part of the reason that pwMS produce anti-neurafilments
antibodies.

We have known that there are damaging antibodies in the CSF because when we purified them and then injected them into the brains of meeces it was not a pretty sight. So we need to get rid of plasma cells from the CNS and the body to cut down antibody production.

None of the anti-B cell antibody treatments will do this effectively although anti-CD20 can block the production of cells that will become plasma cells, but there is a way and yes you can guess what I will say. So are you up for a study? 

We (I mean ProfG & DrK) have been discussing this for a while and hope we can get people, who have been ignored for trials, into a study to test this idea and hopefully save some brain in the process. Who is going to fund it?

10 comments:

  1. This seems like a fairly obvious idea. Why didn't someone do this 10 years ago? Is there some technical barrier that the authors overcame?

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  2. Dear MD,

    There is a lot of evidence appearing proving the immune response. Have those that believe otherwise (can I call them immunofoes?) started to come round?

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    1. Doubt it immunfoes could argue it is a consequence as could immunofriends

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  3. I have an "idea" for financing this study .... Probably you Team G have already thought of or tried it, but how about sending the draft study as project financing seeker assisted by the Bill and Melinda Gates Foundation, or for Ann Romney Center for Neurological Disorders? ...Ann Romney, wife of the former candidate to the USA Presidency, Mitt Romney, has particular interest in research on MS because she also has the disease ...

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  4. Excellent post. We finally seem to be getting somewhere. Good to hear that thought is being given to a trial. However the hope is always killed off with the usual "who is going to fund it". My first boss use to say "bring me solutions not problems". A special tax on neurologists say 5 percent would raise £10 million. It's the least they can do given that only a tiny proportion of their patients regain their health.

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  5. Do you have a target figure in mind?

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  6. see also http://www.ncbi.nlm.nih.gov/pubmed/26489686?dopt=Abstract

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    1. Thanks t his shows that there are few original ideas and once tecnology comes along you have people doing the same thing. Good thng it it shows the same result so gives confidence that antibodies to myelin is not the problem.

      Time for some dinosaurs to have a rethink?

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