B Cells Story getting better if you know where to look

Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and Other CD20 B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017. doi: 10.1007/s13311-017-0557-4. [Epub ahead of print]

Selective depletion of CD20+ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS-a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab.

Prof Hauser is part of the “Rumble in the Jungle” which is the “burning debate” at ECTRIMS 2017. This puts two heavy weight immunologists/neurologists against other hopefully we can stream this live from Paris. 

In the Blue corner we have Prof David Hafler from Yale, USA leading the charge of “MS is a T cell disease”. In the Red corner we will have Prof Stephen Hauser from San Francisco USA leading the “MS is a B cell condition”. The ring master is Prof David Wraith from Birmingham, UK. 

This current paper is by Prof Hauser and is a review article on B cells. I wondered, if was going to be the basis for a strategy of the approach to be used in the debate?…

Hope not, as this is zzzzzzzzzzzzzzzzzzzzzzzzzing. 

The paper is a simple review on the observations around the clinical trials, which has been written loads of times before.

There is not much data supporting any idea of  how the therapies are actually working, but we get the standard sitting on the fence

It’s an anti-T cell agent killing a miniscule population of T cells….really:-( 

It then states that following B-cell therapy, “repopulating B cells consist of larger
numbers of naïve B cells and fewer antigen-educated memory
B cells and plasmablasts, possibly explaining the
continuing suppression of MS disease activity noted even after
B-cell reconstitution has occurred”.

So not a lot to tell you what is going on.

Clearly our view that memory B cells are important targets has not yet gained traction.

Maybe people can’t be bothered to read it……What you haven’t read it yet. It’s here and free.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50

So maybe it sounds like we need to shout a bit louder, so that people start to try and disprove the idea…However, so far this year it was not been difficult to build on the idea.

However, when I was presenting the data a couple of weeks ago, someone asked how does it fit into the idea that oligodendrocytes are the major target in MS.

I waffled a rubbish answer and good point I thought.

If CD4  T cells are the cause of  problem one also has to struggle to answer the question too. Why? Because oligodendrocytes do not express MHC class II (a restriction element for CD4 T cells. See the education posts) in vivo and so are not going to be targeted by CD4 T cells directly so its effect would have to be indirect.

Whilst those bothered that CD4 TH17 cells are the problem can ponder this question, it is evident that B cells make factors that can kill oligodendrocytes and nerves.

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 Aug 15;309:88-99.

B cells mediate multiple sclerosis (MS) pathogenesis by mechanisms unrelated to immunoglobulin (Ig). We reported that supernatants 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 (twice the size of an IgG antibody molecule and much bigger than typical cytokines) could contribute to damage within the central nervous system by secreting molecules toxic to OL and neurons.

The previous paper I had forgotten about  Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb S, Fan B, Ouamara N, Johnson TA, Rajasekharan S, Bar-Or A.Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol. 2012; 246(1-2):85-95. B cells are important in the pathogenesis of multiple sclerosis (MS) and some of the effects are not dependent on maturation of B cells into immunoglobulin (Ig) producing plasmablasts and plasma cells. B cells present antigen, activate T cells, and are involved in immunoregulation and cytokine secretion. To determine if B cells from MS patients secrete products that have deleterious effects on glial cells not mediated by Ig, and to compare effects with secretory products of normal controls (NC), we isolated B cells from 7 patients with relapsing remitting MS (RRMS) and 4 NC. B cells were cultured alone or after stimulation with CD40 ligand (CD40L), CD40L+cross-linking of the B cell antigen receptor (xBCR) and CD40L+xBCR+stimulation of toll like receptor 9 (TLR9). Supernatants were harvested and incubated with mixed central nervous system (CNS) neonatal rat glial cells. Supernatants from unstimulated NC B cells induced on average death of 7% (range 0-24%) of differentiated oligodendrocytes (OL); in contrast, supernatants from unstimulated B cells from RRMS patients induced death of 57% (range 35-74%) of OL. Supernatants of stimulated B cells from NC did not increase the minimal OL death whereas stimulation of B cells from RRMS had variable results compared to unstimulated B cells. Supernatants from both NC and RRMS induced microglial enlargement and loss of normal resting bipolar morphology. OL death did not correlate with levels of tumor necrosis alpha (TNF-α), lymphotoxin alpha (LT-α), interleukin 6 (IL-6), IL-10, transforming growth factor beta 1 (TGF-β1) or any combination or ratio of these cytokines. Analysis of 26 supernatants from NC and RRMS patients failed to detect IgM. There were very low levels of IgG in 8 of the 26 supernatants, and no correlation between of OL death and presence or absence of IgG. Sera used in both the B cell and glial cell cultures were heated, which inactivates complement. The effects of B cell supernatants on OL could be direct and/or indirect involving either microglia and/or astrocytes. The identity of the toxic factor(s) is as yet unknown. Thus we have demonstrated that B cells from patients with RRMS but not NC secrete one or more factors toxic to OL. It is possible that such factors produced by peripheral blood B cells when within the CNS could contribute to demyelination in MS patients.

Whats is the factor? I don’t know but more of a focus for B cells

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  • T cells? Still being debated? Fair enough, look forward to hearing all about it.

    Meanwhile sounds like one for Holmes and Watson. The case of the mysterious molecule(s) secreted by B cells. First question, which B cells? Not yet matured into plasmblasts and plasma cells, could it be the ebv infected memory B contingent?

  • One imediate conclusion not related to your reasoning is that
    "no correlation between of OL death and presence or absence of IgG."
    So much so for the usefullness of oligoclonal bands predictive value at least in this setting

  • That is why my doubt remains.

    I read yesterday part of this study and wondered if for example, and for a reason still unknown, a virus could hide in the progenitor cells of oligodendrocytes, and perhaps secrete some substance, a protein, that would cause the OPCs to stop migrating for which they would have been recruited and this would cause them not to mature in oligodendrocytes proper?
    That's, the virus might not even cause the disease but could aggravate the disease, demyelination in those who were infected with it, since it would prevent the maturity of the OPCs.

    As far as I understand from the study they tested about 40 substances related to inflammation, and could not identify any factors that caused cell death.

  • According to barts blog black swan theory those human b cells form controls and rrms patients must have the ebv virus in them ,right?
    So does that influence the outcome?

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