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Another interesting story can be found on http://www.msrc.co.uk/ it tells that FTY720 seems to have anti-viral potential - at least in low doses.
Again there may be questions raised regarding an infectious cause of MS...

Just a thought, could it be that immune-system-rebooting (Campath / HDC) acts through killing the infected host-cells of EBV (B-cells) and thereby eliminating the EBV infection, and thus maybe the primary dissease cause?
In this context it might be interesting to see how the HDC following treatment with Copaxone will be doing.
If MS was autoimmune immunetollerance through Copaxone might be important.
If symptoms do return after HDC because of a reinfection with EBV then Copaxone should be without effect - maybe then one could give INF a try for its antiviral properties.

--Frank



B cells, Epstein Barr Virus and Multiple Sclerosis 12 August 2008
and B Cells

Summary

Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause.

Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells.

Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines.

In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response.

These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies.

Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.

Source: Lancet Neurology 2008; 7:852-858 © 2008 Elsevier Limited (12/08/08)

Frank,

You've hit on something that I have been wondering about recently. When we think of the immune system involvement in autoimmune diseases, it may not be that the immune system is viciously attacking the myelin, or other targets for no reason at all, rather it may be that the immune system is permissive to persistent EBV infections and the B cells may be such good hosts to the EBV that the B cells pick up the EBV from its original site of infection in the body (I believe it is the oronasal area) and then transport the EBV far and wide. EBV enters the B cells via the CD21 surface protein. There are suggestions that the EBV may enter other cell types via non-CD21 routes. So the B cells are not necessarily evil thugs, just dumb mules. They carry it throughout the body, perhaps even through the blood-brain barrier under rare circumstances. If they shed EBV, the EBV could get into other cells. What if some of those other cells had the X chromosome problems I mentioned before (in the "Polyamines" topic four years ago)?

When EBV becomes active, one of the first things it does (particularly by EBNA2) is to activate the host cell's cMYC transcription factor. cMYC
is essential to the start of S phase in cells, the DNA synthesis phase, which the EBV wants to start so it can have its DNA replicated. One of the first targets of cMYC in early S phase is ornithine decarboxylase, the first enzyme in polyamine synthesis. This will create a lot of free polyamines: spermidine and spermine. If the cell has disruption of the X chromosome inactivation, or some duplication of the X such that there are additional active copies of the Xp22.1 region I spoke about previously in the "Polyamine" topic four years ago, then there will be overexpression of spermine synthase and spermidine/spermine-N1-acetyltransferase. This would lead to a reduction in spermidine needed for myelin synthesis and an increase in spermine and acetylspermidine. Polyamine synthesis also reduces S-adenosylmethionine (SAM) needed for DNA methylation. This loss of SAM would open up more genes, including EBV genes for transcription, helping to produce more of the packaged EBV viral particles getting ready for cell lysis. I mentioned previously about mouse models of neurodegeneration (Quaking and Jimpy mice) where there is an imbalance in the spermidine/spermine ratios and amounts, favoring more spermine.

There seem to be a lot of things coming together here: the female predominance suggesting X chromosome involvement; the high rate of EBV associated with MS (and other autoimmune diseases); and the way in which polyamines seem to keep popping up with regards to mouse models and reduction in autoimmune symptoms in mouse models (DFMO, an inhibitor of ornithine decarboxylase suppresses a mouse lupus-model; MTA or methylthio-adenosine, an inhibitor of spermine synthase, reduces a neurodegeneration model).

This is a really complicated explanation but the pieces are fitting, with some gaps still.

In cancer there is Knudsen's two-hit hypothesis: that there need to be at least 2 mutation/deletion type events in a cell for it to become cancerous, ex. two different genes go haywire: a suppressor gene gets knocked-out and then one of the genes it is supposed to suppress gets mutated into over-expression. Perhaps there is a two-hit hypothesis for MS: chromosome abnormalities in a cell and then EBV infection into that cell. Most people with EBV tolerate it, but perhaps a few cells in a few people leads to MS.

Wesley

great post, Doc, thanks

BioDocFL wrote:
This is a really complicated explanation but the pieces are fitting, with some gaps still.

Perhaps there is a two-hit hypothesis for MS: chromosome abnormalities in a cell and then EBV infection into that cell. Most people with EBV tolerate it, but perhaps a few cells in a few people leads to MS.

Wesley

Wow...thanks for the explanation, Wesley. Interesting to see how this theory of MS can fold in genetics, female prevalence, and EBV. Yes, it's complicated, but it makes absolute sense. Now get back in the lab!
AC