Maybe not black swans but falcons

Lisak RP, Nedelkoska L, Benjamins JA, Schalk D, Bealmear B, Touil H, Li R, Muirhead G, Bar-Or A. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J Neuroimmunol. 2017 ;309:88-99

B cells mediate multiple sclerosis (MS) pathogenesis by mechanisms unrelated to immunoglobulin (Ig). We reported that supernatants (Sup) from cultured B cells from blood of relapsing remitting MS (RRMS) patients, but not normal controls (NC), were cytotoxic to rat oligodendrocytes (OL). We now show that RRMS blood B cells, not stimulated in vitro, secrete factor/s toxic to rat and human neurons. Cytotoxicity is independent of Ig and multiple cytokines, not complement-mediated, and involves apoptosis. The factor/s have an apparent mw of >300kDa. B cells could contribute to damage within the central nervous system by secreting molecules toxic to OL and neurons.
ProfG has been saying that EBV in B cells may be a black swan but maybe the B cells are killing by themselves. The question is what is the killer protein.

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  • "…maybe the B cells are killing by themselves."

    Of course they do. They enter through a BBB breach into an area of destroyed myelin and half-dead oligos. So they produce the necessary messages to clear the debris.

    The question is, why is there a BBB breach of security in the first place? If BBB is intact, B cells can't enter and can't get excited against CNS.

    • Having spent some time earlier in my career examining the migration of lymphocytes across the blood brain barrier I can report there is no breach necessary, activated lymphocytes adhere to the specialised endothelial cells lining the venules of the brain which then actively participate in pulling the lymphocytes through the endothelial cell. Over a period of time with more migration the integrity of the BBB is eventually compromised.

    • Are you talking specifically for B cells?

      Let's say you are right. Then, what is the rate of infiltration without prior BBB breach? Is it enough to account for the immune cell populations seen in early MS lesions?

      Still, the fact that B-cells are excited simply raises the question why. Autopsy studies (yes, Prineas again) reveal damage in virtual absence of lymphocytes. How can this fit to your views?

    • No, lymphocytes in general. Blocking the initial adhesion of the lymphocytes to the cerebral endothelium is how Tysabri works.
      As I said before this is what happens initially, once migration occurs a number of times the BBB eventually breaks down in this area.
      As I remember, the Prineas study was a unique observation that may not be typical of the majority of MS cases.
      Now you may be right, we're in chicken and egg territory here that there may be some trigger inside the CNS to activate the CNS endothelial cells to express adhesion molecules to bind activated lymphocytes. What this might be is still open to conjecture and difficult to prove.

    • Vasilis, if immune cells are trying to clean up the debris from a more basal pathological process, they are not doing a very good job. We've seen enough studies to know that stopping the immune system mediated inflammation positively affects the course of the disease, potentially considerably.

      It's good you're skeptical of the pure autoimmune hypothesis. But you shouldn't latch on to CCSVI, at absolute best it's a small factor, because we know people treated with it mostly aren't cured. Use your brain to figure out what the underlying neurodegenerative process is.

      Retinal nerve fibres are damaged in MS and they have no myelin. Demyelination is a common outcome of damage to the requirements of brain cells to thrive, for example delayed massive white matter demyelination can occur after hypoxia, but you wouldn't call hypoxia is a disease that is directed against myelin.

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