Thursday, 20 December 2012

Research: B cell follicles driving progression

#MSBlog: Is EBV the cause of MS? I think so. 

Epub:  Magliozzi et al. B-Cell Enrichment and Epstein-Barr Virus Infection in Inflammatory Cortical Lesions in Secondary Progressive Multiple Sclerosis. J Neuropathol Exp Neurol. 2012 Dec

Background: Gray matter lesions are thought to play a key role in the progression of disability and cognitive impairment in MSers, but whether gray matter damage is caused by inflammation or secondary to axon loss in the white matter, or both, is not clear. 


Methods: In an analysis of postmortem brain samples from 44 cases of secondary progressive MS, 26 cases were characterized by meningeal inflammation with ectopic B-cell follicles and prominent gray matter pathology; subpial cortical lesions containing dense perivascular lymphocytic infiltrates were present in 11 of these cases. Because intracortical immune infiltrates were enriched in B-lineage cells and because we have shown previously that B cells accumulating in the MS brain support an active Epstein-Barr virus (EBV) infection, we investigated evidence of EBV in the infiltrated cortical lesions. 

Results: Cells expressing EBV-encoded small RNA and plasma cells expressing EBV early lytic proteins (BZLF1, BFRF1) were present in all and most of the intracortical perivascular cuffs examined, respectively. Immunohistochemistry for CD8-positive cells, granzyme B, perforin, and CD107a indicated cytotoxic activity toward EBV-infected plasma cells that was consistently observed in infiltrated cortical lesions, suggesting active immune surveillance. 

Conclusions: These findings indicate that both meningeal and intraparenchymal inflammation may contribute to cortical damage during MS progression, and that intracortical inflammation may be sustained by an EBV-driven immunopathologic response, similar to findings in white matter lesions and meninges.

Temporal profile of serological changes post EBV infection. The anti-EBNA1 response is predictive of disease activity.

"These results will almost certainly be controversial. Other researchers can't seem to reproduce this groups findings. We will need to wait and see if these results are reproduced. Despite this controversy there is mounting evidence that EBV is strongly associated with MS and some investigators, including myself, believe this association is causal. That has therapeutic implications in that if you prevent EBV infection you may be able to prevent MS or if you target EBV with an anti-viral drug you may suppress MS disease activity. This is what we are trying to do with the Charcot Project." 

9 comments:

  1. This is great news, and if you believe in the EBV causation hypothesis for MS progression I really wish you all the luck on the Charcot project (for our sake, of course ;-)).

    I have come accross this recent study published by Pubmed from the Kanazawa university stating that Resveratrol may be benefitial against EBV and overgrowth of B-cells. May I ask you your opinion on it?

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    1. Sorry, I forgot to attach the link: http://www.ncbi.nlm.nih.gov/pubmed/23251493

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    2. The study looks at essentially one dose which is 50 micromolar, below this it does not do much so the question is how relevant is this concentration? Is it achieved in humans when this is given the molecular weight of resveratol is 228 so one molar is 228g in a litre.
      The relevance then depends on the affinity of resveratol for its target if it were in nano molar range and you only see effects at 50000 times more then is it relevant?

      For cannabinoids for example if I see things happening only about ten micomolar then it is probably not relevance biologically as the compounds do funny things to cells, it is like putting a cell in lard. You need to do some homework and find out if this concentration is achievable....from wine I doubt it

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  2. Prof G

    What's the latest on the Charcot Project?

    A few years ago I had shingles (another example of a virus misbehaving in the nervous system). I was treated with anti-virals, so surprised that no-one has tried this in MS.

    Regarding reproducing the results of the above study, why can't you set this as Mouse Doctors main work in 2013?


    Have a good Christmas break. Perhaps the blog could shut down from Christmas Eve to the 2nd January. This would give you guys a well deserved break.

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    1. Charcot project..why not come to the research day...

      FYI Trial went for ethical review...what trial need to come to research day.

      EBV does not infect mice, so it can't be done in mice and we also have our own interests.

      Prof G is on-call for Christmas...so who knows what he may come up with, so it will be worth a visit

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  3. Strange that it is only this group that seems to find "B-cell follicles" when nobody else does. A touch of the Berlusconi's perhaps?

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  4. Are this group using a different technique to others? Have people tried to exactly replicate these studies?

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    1. They have with the same tissue samples but with no success.

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  5. I hope the Charcot project is successful. The EBV hypothesis could be it.

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