Friday, 2 November 2018

B cells in MS

Today I post on the pathology of the active MS lesion, which we missed in the summer
Machado-Santos J, Saji E, Tröscher AR, Paunovic M, Liblau R, Gabriely G, Bien CG, Bauer J, Lassmann H. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain. 2018 Jul 1;141(7):2066-2082. doi: 10.1093/brain/awy151.

"Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations"...(What a load of Tosh!!!. The referee should be hung, drawn and quartered for allowing this comment to slip by. It is the type of irritating comment now used often by opinion-leaders to re-invent the wheel. They simply ignore the past and pretend what is being presented is novel otherwise the journals would not accept them. Worst thing is they also forget their own work. We know that CD8 T cells are the predominant cell type in MS and that there are B cell rich lesions we have been told this before.


Höftberger R, Leisser M, Bauer J, Lassmann H. Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis ? Acta Neuropathol Commun. 2015 Dec 4;3:80.
In this study we analyzed in detail the immunopathology in archival autopsy tissue of a patient who died with an MS like disease after repeated exposure to subcutaneous injections of lyophilized brain cells. The pathology of this patient fulfilled all pathological diagnostic criteria of MS. Demyelination and tissue injury was associated with antibody (IgM) deposition at active lesion sites and complement activation. Major differences to classical EAE models were seen in the composition of inflammatory infiltrates, being dominated by B-cells, infiltration of IgM positive plasma cells, profound infiltration of the tissue by CD8(+) T-lymphocytes and a nearly complete absence of CD4(+) T-cells. Our study shows that auto-sensitization of humans with brain tissue can induce a disease, which closely reflects the pathology of MS.


Anyway rant over back to the abstract.....
In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. 

A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen’s encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. 

Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. 

The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen’s encephalitis. 

Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.

So the study says CD8, CD4 T cells and CD20 B cells are more common in:
  • In MS than in Health
  • In relapsing MS than Progressive MS
  • In active Lesion rather than Inactive Lesions
CD8 massively outnumber  CD4 T cells by 86%.


 
CD8 T cells are the major subtype in the brain tissue (parenchyma).
This suggests there is a virus being hunted. Is it EBV? JCV?

CD20 B cells are common within the perivascular cell cuff, which we know in EAE is associated with the development of active disease.  So is this the MS lesion?.

CD4 T cells are outnumbered and do not appear to be the Top Dogs. 

They are probably their to help CD8 T cells to be cytotoxic, to help B cells to drive demyelination and help them become antibody producing cells and to help macrophages and microglia to cause damage and to clear up the myelin debris. Maybe it is time to call them Helper/Indcer cells again.

6 comments:

  1. This is a very interesting one....

    https://www.ncbi.nlm.nih.gov/m/pubmed/30173916/

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    Replies
    1. MD posted on this here;
      http://multiple-sclerosis-research.blogspot.com/search?q=Memory+B+Cells+Activate+Brain-Homing%2C+Autoreactive+CD4%2B+T+Cells+

      Delete
  2. If this is a virus we keep talking about, what is the explanation why single application of HSCT works for so many years (e.g. Ottawa-trial)? If EBV lives within B-cells, CD20 antibodies would work as an induction therapy too? And again, has antiviral therapy been tested against MS in clinical studies? And last question, is antiviral therapy been used along Campath-treatment to prevent viral outbreaks, possibly making the effect rather than lymphocyte-depletion? Oh man, I start to think this will turn out to enter the history of crappy medicine only second after lobotomy for psychological problems. Who is the Ancel Keys in MS research and who is buggering up the scientific training for medical doctors?

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  3. "This suggests there is a virus being hunted"

    Sorry no virus

    :(



    CSF B-cells in relapsing multiple sclerosis are driven towards a similar,
    antigen-experienced, inflammatory fate

    We identified memory and plasmablast clonal connections (including identical clones) between patients across the CSF and periphery, dominated by IgA, IgG and IgM immunoglobulin subclasses. We identified pro-inflammatory profiles of CSF plasmablast B-cells that distinguish them from their peripheral counterparts and other CSF B-cell subsets. Finally, we detected no viral transcripts, including Epstein-Barr virus, in the B-cells (n=70 B-cell subsets)

    Our findings support the hypothesis that B-cells originating in the periphery undergo clonal expansion and sustain a pro-inflammatory shift in the CSF in MS, without detectable viral infection.

    http://www.professionalabstracts.com/ectrims2018/iplanner/#/presentation/1608

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  4. "Sorry no virus :("

    EBV in microglia and astrocytes
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192109

    emailed the study to MS/EBV researcher..response:
    "Four independent studies have identified EBV-infected B cells in histological sections of the brain in MS although several papers have failed to detect EBV in brain tissue. In the below study the authors did not detect EBV-infected B cells in the CSF. Further studies with other techniques are needed to assess the frequency of EBV-infected B cells in the CSF in MS."

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  5. Mixed results

    Programmed death 1 is highly expressed on CD8+ CD57+ T cells in
    patients with stable multiple sclerosis and inhibits their cytotoxic
    response to Epstein–Barr virus

    "We demonstrate that polyfunctional
    cytotoxic CD8+ CD57+ T cells are able to kill EBV-infected cells in
    healthy donors. In contrast, an anergic exhaustion-like phenotype of
    CD8+ CD57+ T cells with high expression of PD-1 was observed in inactive
    patients with MS compared with active patients with MS or healthy
    donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory
    infiltrates from post-mortem MS tissue confirmed the association of this
    cell phenotype with the disease pathological process. The overall results
    suggest that ineffective immune control of EBV in patietns with MS during
    remission may be one factor preceding and enabling the reactivation
    of the virus in the central nervous system and may cause exacerbation of
    the disease."

    The authors of the study say

    However,
    the results from other studies examining the involvement
    of EBV infection in the MS pathological process diverged.
    EBV was undetectable in a heterogeneous B-cell infiltrate
    in white matter lesions (both adult and paediatric MS)
    and in B-cell infiltration within the meninges and
    parenchymal B-cell aggregates in MS brain tissue.14 In
    another study, EBV-specific transcripts were not detected
    in active and chronic active MS plaques rich in perivascular
    B-lymphocyte cuffs or in single B lymphocytes and in
    plasma cells isolated from MS patients’ CSF.15 The negative
    results raised questions about the prevalence of active
    EBV infection in MS brain.

    No consensus

    :(

    https://onlinelibrary.wiley.com/doi/full/10.1111/imm.12808

    Obrigado

    ReplyDelete

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