How are B cells involved in MS

H

This is a review and I dont normally post reviews but it gives a different take, but it is different based on the figure below

  • Accumulating neuropathological, serological and immune cellular evidence strongly suggests that B cells are involved in the pathophysiology of multiple sclerosis (MS).
  • Specific B cell subsets seem to be involved in MS as antigen-presenting cells and pro-inflammatory cytokine-producing cells; other B cell subsets serve as anti-inflammatory regulatory cells.
  • The persistently active infection of B cells with Epstein–Barr virus could lead to CNS damage; however, the causative role of the virus in MS remains controversial.
  • Treatments that target B cells are effective in MS, which strongly suggests the involvement of B cells in disease pathophysiology.
  • Autologous haematopoietic stem cell transplantation is known to have regenerative effects on T cells and limited evidence indicates that the treatment leads to repopulation with predominantly naive B cells.
  • The effects of therapies on B cell subsets provide insight into the roles of B cell populations in disease; further immunological studies are required to improve our understanding of these roles.

Cencioni MT, Mattoscio M, Magliozzi R, Bar-Or A, Muraro PA. B cells in multiple sclerosis – from targeted depletion to immune reconstitution therapies. Nat Rev Neurol. 2021 Jun 1. doi: 10.1038/s41582-021-00498-5.

Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein-Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects – with a focus on the effects on B cell subsets – of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.

This is figure 1. It is all very complex for something very simple. This suggests what happens after treatment

MS rituximab ocrelizumab alemtuzumab HSCT

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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10 comments

    • I wonder whether it is reading and understanding?:-(……the pie charts are the proportions of B cells subsets on treatment, rituximab shrinks the memory B cells and expands the B regulatory cells or as I sometimes call them the immature B cells that produce IL-10 to grow….ocrelizumab on the other hand expands the memory cells massively. T helper cells plummet with both anti-CD20s…Why would they work so differently. If you deal with absolute numbers verses proportions the effects are clearer, more consistent. If the HSCT and B cell gurus think it is all so complex, do meer mortals stand a chance of understanding anything/

      • If I were to draw the pie charts it would be different….well I wouldn’t draw a pie chart for a start. In the examples above in the controls there are 70 naive cells and 50 memory cells and 5 regulatory cells. Rituximab you have depletion so it is not the same and now it could be in rituximab you have 7 regulatory B cells, 4 naive B cells and 1 memory B cells. So if you work in proportions you get a different view. In ocrelizumab you have 60- 70% memory B cells in the B cell pool…well this does not fit willl any of the published data i.e. ours. Memory cells are depleted massively

    • It is the same paper as the one above

      The ideas are there, but it seems like you have to swim through treacle to make sense of them. I guess I don’t get it may be if I start a manta that “It’s all T cells” and so so complex I will but where do you start?

      “After the administration of rituximab, a dose-dependent depletion of circulating CD20+ B cells rapidly ensues and persists for several months. A small subset of CD20+CD3+ T cells is also depleted by rituximab in patients with MS. The function of this T cell population is unknown but they have been proposed as contributors to the pathogenic process in MS, in which case their depletion could partly account for the action of CD20-targeted therapies”.

      “As with rituximab, the radical depletion of B cells occurs within 2 weeks after the first ocrelizumab infusion. Preliminary analysis of blood from a small group of participants in the OPERA I trial indicated that a small number of B cells remain detectable in the peripheral circulation after treatment with ocrelizumab, characterized by a memory class-switched profile with a low diversity of BCRs. CD20-expressing T cells, which one study has suggested make up nearly 20% of all CD20-expressing cells (including B cells), are efficiently depleted in addition to B cells, suggesting that the clinical efficacy of ocrelizumab might not only be mediated by effects on B cells”.

      I wonder if this paper was T celled by the referees or whether it was put there. Hey Ho

      • Sorry, I should not have read on my phone…

        Google threw two B cell papers at me earlier today and I made a mess.

  • All B cell depletes cannot be created equal.

    Some anti CD-20 seam to be more effective than others from the trials. Between the 3 currently available the data is all different and pipeline Ublituximab seams to be even more effective at reducing relapses.

    I wonder which B cell depletion therapy is most effective against progression, is there any data on this?

    • They are indeed not created equal….rituximab is out of patent it is more immunogenic because it has more mouse, Ublituximb was developed to be more like ocrelizumab and has a enhanced cellular killing mechanism, ofatumumab is being used subcutaneously. I dont think you can compare one trial to another and get anything more than a trend. However I am not sure you can make a claim it is better. As for effects on progression without a head to head study it is hard to say they are different….It is all dose dependent, Twice as much ocrelizumab on a dose per kg basic is better than itself. thirty times more ocrelizumab is less immnogenic than itself. Ocrelizumab is a more potent B cell depleter at the dose used than rituximab, other antibodies such as Obinutuzumab are more potent apoptosis (cll suicide inducing). Lets see the depeltion data for ublixituximab at the approved dose

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