The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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EBV-specific CD8 cells in CSF

Discussion in 'Other Health News and Research' started by Ecoclimber, Jul 27, 2015.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Premission to repost by Prof. Gavin Giovannoni

    There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

    Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

    EBV-specific CD8 cells in CSF

    van Nierop GP, Mautner J, Mitterreiter JG, Hintzen RQ, Verjans GM. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins.Mult Scler. 2015 Jun 3. pii: 1352458515588581. [Epub ahead of print]

    BACKGROUND:
    The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) may involve intrathecal EBV-specific T-cell responses targeting the virus or indirectly, autoantigens.

    OBJECTIVE:
    Compare the prevalence and fine-specificity of EBV-specific T-cells in the cerebrospinal fluid (CSF) of patients with MS (n = 12), clinically-isolated syndrome (CIS) (n = 17) and other neurological diseases (OND) (n = 13).

    METHODS:
    Intrathecal EBV-specific T-cell reactivity was assayed using CSF-derived T-cell lines (CSF-TCL) and autologous EBV-transformed B-cells (autoBLCL) as antigen-presenting cells (APC). EBV proteins recognized by autoBLCL-specific CD8 T-cells were identified using human leukocyte antigen class I (HLA-I)-negative monkey cells as artificial APC, co-transfected with 59 different EBV genes and the corresponding patient's HLA-I alleles that were involved in autoBLCL T-cell reactivity. Reactivity towards the MS-associated autoantigen αB-crystallin (CRYAB) was determined analogously.

    RESULTS:
    CSF-TCL from CIS and MS patients had significantly higher frequencies of autoBLCL-reactive CD4 T-cells, compared to the OND patients. CIS patients also had significantly higher autoBLCL-reactive CD8 T cells, which correlated with reactive CD4 T-cell frequencies. AutoBLCL-specific CD8 T-cell responses of four CSF-TCL analyzed in detail were oligoclonal and directed to lytic EBV proteins, but not CRYAB endogenously expressed by autoBLCL.

    CONCLUSIONS:
    Enhanced intrathecal autoBLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in two CSF-TCL, suggested a localized T-cell response to EBV in patients with MS. Our data warrant further characterization of the magnitude and breadth of intrathecal EBV-specific T-cell responses in larger patient cohorts.

    [​IMG]

    Discussion by mouse doctor:

    EBV immortalises B cells and so you can infect B cells to make a cell line to present antigen so you can make a T cell line by stimulating it with its target antigen. They then used these T cells to work out which protein was being recognised by stimulating them with mock antigen presenting cells expressing different antigens. They found more EBV reactive CD4 T cells in the CSF of MSers an more CD8 cells into CISers. There responded to EBV proteins. Is this the main target.

    Rebound occurs after withdrawal of natalizumab and the cells arriving in the brain at this time are going to contain the cells that cause relapse in MS. What are these cells reactive to? EBV, CRYAB or myelin proteins

    1. AnonymousMonday, July 27, 2015 7:32:00 a.m.
      "Rebound occurs after withdrawal of natalizumab and the cells arriving in the brain at this time are going to contain the cells that cause relapse in MS. What are these cells reactive to? EBV, CRYAB or myelin proteins"

      Does everyone coming off Tysabri experience rebound? Does it matter the duration of treatment as to how much of an affect this rebound has?

      MouseDoctorMonday, July 27, 2015 9:40:00 a.m.
      No and if planned right you should not have rebound because you should switch to something else before this occurs.There are lots of posts on the blog about this, however it may have been a missed opportunity to study.

      Tysabri keeps cells out of the brain and it does not kill them, they are there all the time you are on the drug, once it wears off the cells can go back in. I know I havent answered your question but I don't know off the top of my head

    2. [​IMG]
      AnonymousMonday, July 27, 2015 12:12:00 p.m.
      Thanks for replying, another question, I thought Cryab was a *good thing usually in MS, so in what way would this potentially engender a relapse, if coming off Ty ( taking out, going on another medication from the equation). I can see that EBV may play a role and possibly myelin proteins but I don't understand the Cryab connection.

    3. [​IMG]
      MouseDoctorMonday, July 27, 2015 6:44:00 p.m.
      One view it is a break (Steinman view) other view it is a target (van Noort view)

      The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. van Noort JM, van Sechel AC, Bajramovic JJ, el Ouagmiri M, Polman CH, Lassmann H, Ravid R. Nature. 1995; 375:798-801.

      No expression of CRYAB in thymus or periphery so no central or peripheral tolerance to CRYAB so we all have T cells reactive to CRYAB. EBV infected cells upregulate CRYAB so can present antigen and now you have sensitized T cells reactive to CRYAB. Oligodendrocytes stress due to genetics infection EBV, HERV upregulate CRYAB....the rest of the story is inflammation

      or CRYAB down regulates inflammation


      Monday, July 27, 2015 5:51:00 p.m.
      MD, I agree that rebound effect after discontinuation of Tysabri is missed opportunity to study MS. It seems the rebound effect would "turn back the clock" and provide clues on the origin of the disease, e.g. What is going on in the CNS while on Tysabri? And upon discontinuation is there Treg dysfunction?

      MouseDoctorMonday, July 27, 2015 6:48:00 p.m.
      I would suggest the rebound tells us it has nothing what so ever to do with T reg. however Dacluzimab may point to this also.

      Another big question is with tysabri stopping inflammation do the natural repair mechanisms occur, i.e. is the brain full of remyelination or is there long term demyelination

    Also

    Is there really an association between EBV antibodies and antibody Synthesis


    Association of serum Epstein-Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis.
    Pfuhl C, Oechtering J, Rasche L, Gieß RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspächer B, Bellmann-Strobl J, Paul F, Ruprecht K J Neuroimmunol. 2015;285:156-60

    Abstract:
    Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection. A characteristic feature of MS is an intrathecal synthesis of immunoglobulin (Ig)G. In 90 patients with clinically isolated syndromes/early relapsing-remitting MS, serum antibodies to Epstein-Barr nuclear antigen-1, but not to EBV viral capsid antigen, rubella, or varicella zoster virus, were higher (p=0.03) in those with than those without a calculated intrathecal IgG synthesis >0% and correlated with the percentage (r=0.27, p=0.009) and concentration (r=0.27, p=0.012) of intrathecally produced IgG. These findings suggest a link between EBV infection and the events leading to intrathecal IgG synthesis in patients with MS.

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  2. anciendaze

    anciendaze Senior Member

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    Just to help those who may not have been following this subject: CIS (clinically-isolated syndrome) is something that would be classified as MS if it were not isolated. It is predictive of later MS.

    There are problems in standard measurements of antibodies to EBV. We now know that people with MS often have strains of EBV which are different from those commonly found in healthy people. Second, there is some evidence EBV has the ability to manipulate immune response to protect itself. This means these responses may not be reliable indicators in chronic disease states.

    Considerably more is going on in immune response to EBV than is covered by standard assumptions about humoral immune response in peripheral blood. We need a much better understanding of what is actually taking place in signalling between immune cells.
     

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