Monday, 23 October 2017

Programmed Death 1 disappears and leaves EBV to trigger Activity

Now that we know what PD-1 is, it's time to look at this paper


Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, Borsellino G, Battistini L, Muraro PA. Programmed death 1 (PD1) is highly expressed on CD8+ CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus. Immunology. 2017. doi: 10.1111/imm.12808. [Epub ahead of print]

We know that virtually everybody with MS is infected with Epstein Barr Virus. Most people are as it is very common in humans.

We get infected through saliva. It then infects B cells and makes them proliferate like crazy and turn into memory B cells. The virus then shuts down and hides in the B cell, where it is not going to do much damage. But every now and then the virus activates, and sheds live virus. The immune response recognises the virus and kills the infected B cells and things all quieten down.

In Australia they are making T cells that will kill EBV, based on a very small, unreproduced study stating that it may influence the activity of MS.

MS and the CD8 that attack anti-EBV viral T cells 

A subset of CD8 cells express CD57  - which is
an enzyme - (Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1-B3GAT1) that recognises sugar molecules and is involved in the destruction of chemicals, and I guess viruses.


In healthy individuals they killed EBV infected cells but in stable MS these cells also expressed PD-1, suggesting that they had become immunologically exhausted so they were not killers, but in active MS the CD8 cells had PD-1 and were killing. 

This suggested that when MS is stable they do not control the EBV infection, maybe because it is at a silent stage, but this may enable the re-activation of virus, which could trigger disease. 

Is the disease caused by the attack of virus?. 

The question is, is it a cause or really a consequence?


ABSTRACT
Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). 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.

11 comments:

  1. Pd-1 immunne check point is seen in cancer microenvironment where at the border of the lessions t -cell look "exhausted"

    Cancer immunotheraphy of today research what they what to do is take

    the "brakes" of the immune system and just let go

    I am thinking about the recently aprooved new hype Car-t cell

    theraphy that do just that

    Of course no one knows what will be the side efects of turbocharged the immune system like that .Most likely new autoimmune disease on top of a cancer context

    However this is even more pressing in the context of ms as we dont need a overdrive immune system that can do us even more harm
    What will be the side efects of those engineer cd8 cytotoxic t cells in the context of ms?


    "T-cell exhaustion is a hyporesponsive state of T cells in chronic environment, with increased inhibitory receptors, decreased effector cytokines and impaired cytotoxicity.
    Most T cells in tumor microenvironment are exhausted, leading to cancer immune evasion.
    PD-1 is the major inhibitory receptor regulating T-cell exhaustion, T cells with high PD-1 expression lose the ability to eliminate cancer.
    Reversing T-cell exhaustion represents an inspiring strategy to treat cancer"

    http://www.nature.com/cddis/journal/v6/n6/full/cddis2015162a.html

    Obrigado

    ReplyDelete
  2. "Open Questions

    What is the definition of ‘exhausted T cell’?
    What is the differentiation process of T cells in tumor microenvironment?
    How does tumor microenvironment regulate T-cell exhaustion?
    Reversing T-cell exhaustion represents promising cancer therapy, what are the limitations and adverse reactions? How to improve treatment efficiency?
    What should be further studied about T-cell exhaustion?
    What are the similarities and differences between T-cell exhaustion in chronic infection and T-cell exhaustion in cancer?"

    ReplyDelete
    Replies
    1. What is the definition...go read the previous post on immune check points and there is a link to exhaustion.

      Talking about cancer is off topic

      Delete
    2. "Talking about cancer is off topic"

      Funny when all the drugs are cancer drugs
      with Copaxone being the ms specific exception.

      Delete
    3. You forgot some like natalizumab however if we start talking about cancer biology we will have to call overselves Bart's we do everything.com

      Delete
    4. You are right Md

      And i understand that we need to focus on Ms

      But you know that most (not all) hi eficaccy ms drugs

      (even hsct)have start with cancer research later adaptation to ms

      Team G excelent work on the latest approved Cladribine is the

      perfect example of such drug

      I am sure that team G look at cancer patients efect of the

      drug before take it to ms and you post such cancer study here

      in the blog

      The early days of Cladribine: pharmacokinetics in people with lympho-proliferative disorders

      http://cladribine4ms.blogspot.pt/2016/01/the-early-days-of-cladribine.html

      http://multiple-sclerosis-research.blogspot.com/2016/01/the-special-one-cladribine-acting-in-cns.html

      Obrigado

      Luis

      Delete
    5. I understand the restriction proposed by the MD, because otherwise the debate will become very broad, but I also understand Luis, because, for example, when dealing with Lymphomas the onconcologists can offer help in understanding the EBV activity.

      This was even something I asked myself about these days: Novartis has launched a more specific type of cancer immunotherapy, specifically against Leukemia, which makes supercompetitive, super-responsive T and B cells. Would we have as a side effect of this therapy autoimmunity?
      One has to think about this even to actually close certain questions about autoimmunity and EBV.

      Delete
  3. Cinara i have talked to my hematologist here in portugal and he say

    that Car-t cell theraphy is in it infancy (it cost 500 000$)

    And at this moment we dont know the side efects of "turbo charge" the immunne system

    Obrigado

    ReplyDelete

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