Monday, 27 June 2016

ResearchSpeak: grey matter lesions

Shooting down the CNS plasma cell; can you help? #MSBlog #MSResearch #ResearchSpeak

"One of the hypotheses in relation to progressive MS is that after a period of time inflammation within the brain and spinal cord becomes independent of peripheral mechanisms. In other words it doesn't matter if you switch off T and B cell activation in the periphery, with potent anti-inflammatory drugs, progressive MS will continue unabated. One of the mechanisms that is hypothesised to explain this is immunoglobulin, or antibody, deposition with complement activation within the CNS. The immunoglobulin is produced by the intrathecal (within the coverings of the brain and spinal cord) B cells and plasma cells. Plasma cells in particular are hard nut to crack. They are long-lived and become independent of T cell help. The seem to live in their own niche and churn out antibody. The antibodies are what we refer to oligoclonal bands or OCBs. All the current DMTs and HSCT don't clear the spinal fluid of these antibodies. This is why our group are now exploring add-on treatments to try and get rid of the OCBs; if we get our funding for a trial we may be asking some of you to help by participating in a t rial. Getting rid of intrathecal plasma cells may be easier said that done. However, where there is a will there is a way and where there is biology there must be a mechanism to target; at least that is what we think."

"One of the ways that antibodies cause damage is that when they bind to their target they activate effector proteins called the complement cascade that then does the damage. The study below shows abundant complement activation within MS lesions. Please note that complement can be activated by other mechanisms that are not necessarily related to immunoglobulin; what we are seeing in this study can't simply be extrapolated back to the OCBs and plasma cells. However, this study and other studies provides us with a compelling case to think about additional add-on strategies for treating progressive MS."



Watkins et al. Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation. 2016 Jun 22;13(1):161. doi: 10.1186/s12974-016-0611-x.

BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression.

METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls.

RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions.

CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.

9 comments:

  1. I really like to see research into progressive MS, the mechanisms and possible therapies. For people like me - who became progressive from evident symptom onset - this is very heartening.

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  2. Do I understand correcty when I say that minor viral infections - cold viruses etc. - can fire up this type of damage, potentially hastening progression?

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    1. In theory any infection that produces pro-inflammatory cytokines which then enter the CNS and stimulate already activated microglial cells could influence the rate of progression. We ned to find a way of returning microglia to a quiescent state. It's only my opinion but I think NSAIDs have a role to play here.

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  3. I came across this abstract indicating that OCBs that were initially detectable in CSF were not detectable after 10 infusions of Tysabri. http://www.ncbi.nlm.nih.gov/pubmed/22041091

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    1. Perhaps some attention should be given to Hailey's comment?

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    2. I am aware about this finding but I am not that the observation is repeatable.

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    3. You must surely have a lot of data yourselves from your own patients?

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    4. I think they've just started using lumbar punctures for post DMT monitoring and even now they're only using it for some not all patients. So no, i wouldn't think they would have too much data from their own practice, some - which has been discussed previously (in a fairly recent entry - unfortunately i'm not able to search for it right now).

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  4. A great thanks to Mr GIOVANNONI and people like him (unfortunately not many enough)that dedicate their lives to save ours and our family's.
    Thanks again for everything.Christina-Thanassis from Athens

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