Memory B cells are there to help CD4 T cells

Memory B Cells present antigen to CD4 T cells in multiple sclerosis, so T cells are on top of the pile and B cells are there to help the baddie T cells. Therefore, the status quo is maintained and everything is super.

However, has the latest autoantigen in MS been found?

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic-, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in an HLA-DR dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.

In MS there are cells that are spontaneously proliferating in the blood. These can be found in the brain of people with MS. The cells that are proliferating are mainly memory T cells and they respond via a mechanism involving MHC class II and they produce interferon gamma (TH1) cells.

The B cells (Switched memory and to some extent non-switched) upregulate HLA-DR and drive the auto proliferation by T cells.

This is proliferation is not blocked by targeting CD40 on the B cells perhaps not surprising if EBV creates CD40 mimicks. However it could be blocked by bruton tyrosine kinase inhibitors. So maybe a mechanism of action of BTK inhibitors. 

They looked at cells found in CNS lesions and this consisted of T cells where it seems that the CD8 cells present are abundant in the periphery also suggesting that they were trafficking in perhaps by a bystander mechanisms. However, there were CD4 clones that may have expanded in the CNS. This study elegantly examined the recognition target of the cells and they recognised nucelotide exchange factors (RASGRPs), notabtly RAS guanyl-releasing protein 2. Other people recognised this target too. Is this the cause of autoimmunity in MS?

A nice piece of work that I have yet to adequately digest but I have my doubts.

Based on Message the target is expressed by nerves but it is is also found in other tissues, including lymphocytes. Is this why there is autoproliferation? 

Anyway a trial is now planned to block the immune response to this antigen. 

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  • "Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells"

    Didn't Pender say Memory B cells present as antigen cells to T cells in the brain back in 2003..? No mention of EBV in this paper though.

  • "there is now
    compelling evidence that MS is an autoimmune disease with
    dysregulated adaptive immunity at its core. Findings from EAE
    and blood cells of MS patients together with the strong genetic
    HLA-DR15 association hint at the importance of myelin-reactive
    CD4+ T cells (Sospedra and Martin, 2005)."

    Here comes the t cell brigade… 🙂

    • I think this paper highlights that MS is a B-cell driven disease. Macrophages are the final component of the disease process, activated by T cells(surely blocking VLA4 on B cells cannot purely explain the efficacy of Nataluzimab), which in turn are activated by B cells.

      If anything this is a "unifying theory".

      MS is clearly not "just T" or "just B" and I do not see why people are hanging on to that dualism. B cells are just upstream, in the same way that atherosclerosis is upstream of heart failure due a myocardial infarction.

      Very impressive work and ties it all together nicely.

    • Natalizumab can not just be B cells but for the past twenty years it has just been about T cells. Natalizumab inhibits them all and monocytes will be an issue just as cd8 are an issue with JC virus.

      Yes there is nice work here but there is also wishfull wishfull thinking. The authors have said what do i think about ms it is a CD4 T cell grey matter disease with B cell antigen presentation.

      The MS being just a grey matter disease is laughable. The picture of the RASGRP2 shows it only in the grey matter so MS must be a grey matter problem.

      Come on the picture is probably artifact of a rubbish antibody, look at the bit cropped the highest staining was in the centre of ablood vessel suggesting endogenous peroxidase issues. As such motor nerves often crop up with such artefact. The staining does not match the published data on message distribution.

      At. ISNI prof Martin said we was going to do a phase I trial with the RASGPR peptide. I doubt RASGRP2 will reproduce as auniversal candidate so the trial fails there and using a technique that has likewise failed to be good enough.

    • Ties it all togehter nicely.

      Scott Zamvil thought this was the best paper at ECTRIMS.Is it too perfect. It simply reinforces what we have been told.

    • haha, morning ramblings of a B-cell believer… I totally agree, B cells are the driver, but when you look at the data on the pathogenesis of the disease OF COURSE T cells are involved(as a/the major effector cell).

      Seems to be a pretty widely expressed protein in the cortex, I would imagine if it was the major antigen stimulating MS disease activity in general then the disease would be more aggressive…A RASGRP peptide surely won't do too much. At least they showed that if there was going to be a magical bullet(with less of a PML risk) it would most likely be B cell focussed.

      However they do conclude…
      "Important questions concerning how the cortical/neuronal expression pattern of RASGRP2 relates to inflammation in the meninges, perivascular spaces, or brain parenchyma, and how the released protein may be distributed via the CSF, remain to be addressed."

  • B cell depletion with anti-CD20 antibodies very effectively reduces
    MS relapses suggesting an important role of B cells
    B cell depletion with anti-CD20 antibodies very effectively reduces
    MS relapses suggesting an important role of B cells

    Mais um tiro?
    No "Black swan"

    One more shot ?

    At the "black swan"


  • In summary, our data link B and T cells with MS pathogenesis
    and show that the interactions of these two cell types probably
    occur in conjunction with the MS-associated DR15 molecules
    and that B cells may express antigens, which are also upregulated
    in the brain and recognized by AP CD4+ T cells.

    Furthermore, they
    provide a plausible explanation for the high efficacy of anti-CD20
    therapy in a T cell-mediated disease such as MS

    This will keep you up at night… 🙂


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