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.

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

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  • "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?

    • 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

    • 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.

    • 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

  • 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?

    • 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

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