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Research Article: 'B cells can drive inflammation in MS'

Discussion in 'Other Health News and Research' started by aimossy, Oct 22, 2015.

  1. aimossy

    aimossy Senior Member

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  2. aimossy

    aimossy Senior Member

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    Paper in the journal 'Science translational Medicine'
    'Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy'

    http://stm.sciencemag.org/content/7/310/310ra166

    @Jonathan Edwards I thought I should tag you on this one.

    Editors Summary:

    "Eclipsing multiple sclerosis
    B cell depletion therapy (BCDT) has been shown to limit inflammation in some cases of multiple sclerosis (MS); however, how exactly BCDT works has remained unclear. Now, Li et al. report that a subset of B cells that produce the cytokine granulocyte macrophage–colony stimulating factor (GM-CSF) contributes to MS pathogenesis. These cells are more frequent in MS patients than in healthy controls and increase proinflammatory myeloid responses. Moreover, production of these cells counterbalances the generation of interleukin-10 (IL-10)–producing regulatory B cells, which are thought to be protective in disease. After BCDT, the ratio of GM-CSF/IL-10–producing B cells is normalized, suggesting that BCDT may work in part by decreasing the number of pathogenic GM-CSF–producing B cells."
     
    Last edited: Oct 22, 2015
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  3. nandixon

    nandixon Senior Member

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    Yes - it's important to consider that B cells not only have antibody and antigen-presenting functions, but additionally they produce cytokines, chemokines and other signaling molecules.

    So depletion of B cells by rituximab may be working in some instances not by (ultimately) reducing autoantibodies, but rather by disrupting signaling mechanisms between B cells and other cells (e.g., macrophages, Tregs, etc.). And this could be true even if the chemical signal being produced by the B cell is not technically abnormal.

    Another interesting example of this concept (i.e., antibody-independent functions of B cells), besides that presented in the article of the original post, is found here:

    A Novel IL-10-Independent Regulatory Role for B Cells in Suppressing Autoimmunity by Maintenance of Regulatory T Cells via GITRL

    The signaling molecule being studied and produced by the B cells in this case is glucocorticoid-induced TNF ligand (GITRL), which was found to maintain (increase) Treg numbers. Thus, treatment with rituximab in this respect can be said to be immunostimulatory, rather than immunosuppressive. This is a mostly unexpected result if one is simply thinking about B cells as only producing antibodies. (Note that this was a mouse study but that the authors were attempting to discover why use of rituximab is sometimes associated with increased or new onset autoimmunity in humans.)
     
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  4. msf

    msf Senior Member

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    Has the delay in improvement of symptoms with Ritux being discussed in this context?
     
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  5. nandixon

    nandixon Senior Member

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    I know that the short-lived plasma cells that produce autoantibodies do not have a monopoly in the human body as being the only cells, immune or otherwise, that have a lifespan of several months. So it may be the death or decrease of other cell types that is corresponding with the apparent delayed improvement seen in ME/CFS with rituximab. (The time period might also correspond to a gradual increase in a cell type or product previously being suppressed as well.)

    On a slightly different note (and maybe off-topic), one of the more interesting possibilities for why ME/CFS has seemed so difficult to get a handle on is the possibility of there existing both immune suppression and autoimmunity simultaneously. This has recently been proposed in at least one seemingly unrelated context:

    The paradox of chronic neuroinflammation, systemic immune suppression and autoimmunity after traumatic chronic spinal cord injury
     
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  6. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Yes, someone else emailed me that paper. The finding of expansion of a cytokine producing subset of B cells in MS patients is interesting and worth repeating. However, there is a dreadful review article on this paper in Science that completely misinterprets the situation relating to B cell depletion, which has nothing to do with interfering with 'other B cell functions'. This is just what the people with the immunological Prada handbags want to convince each other. Complete drivel. We realised that MS was an antibody driven B cell disease in 2000 and tried to set up a trial. Unfrotunately everyone is still obsessed with the idea that it is a T cell disease. (Interestingly the Science review states that without even bothering to give a citation - probably 'cos there aren't any.)
     
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  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Of course I am all in agreement that B cells drive inflammation in MS. But if one were to think what might be the reason why everyone is convinced that it is a t cell disease one might remember that immunohistochemical sections of lesions show T cells but if I remember rightly few if any CD20+ B cells (the same is true of RA in fact in early lesions). That is because T cells are inflammatory migrating cells like neutrophils but B cells are not. Much of the good work on this was done by Margaret Esiri in the 1990s. Now the inflammation in MS is very localised so is due to local cellular activity. And if there are no CD20+ cells there it is a bit mysterious that someone would think rituximab was soothing the local lesion by killing B cells there. (And rituximab does not kill CD20+ cells in the brain very well anyway because of blood brain barrier.)

    Moreover, when rituximab is given to people with MS it is not that they suddenly improve. It is just that they stop having new lesions as long as their blood B cell counts are low. Which presumably means that rituximab is stopping new B cell entry into brain by depleting blood B cells. That might seem to contradict the absence of CD20+ cells in brain, but we know there are plasma cells in brain both in lesions and in perivascular depots. So it looks as if any B cell getting into the brain fairly rapidly turns into a plasma cell if it survives at all. And that is enough to explain the inflammatory role because high local concentration of antibody activates microglia. All sorted.
     
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