Viral Triggers of Relapse


Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, Rosicarelli B, Ruggieri S, Gasperini C, Buttari F, Centonze D, Mechelli R, Salvetti M, Borsellino G, Aloisi F, Battistini L. Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase ofMultiple Sclerosis. PLoS Pathog. 2013 Apr;9(4):e1003220. Epub 2013 Apr 11. 

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS aetiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers (this is a staining reagent containing five MHC class I molecules that are loaded in this case with peptides that mimic EBV molecules and these are bound by CD8 T cells that are specific for EBV), lytic antigen-specific CD8+ T cell (T cells that destroy their targets by rupturing the cell membrane so that the contents ooze out (Lysis) responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.
This study looked for the presence of white blood cells that are reactive to Epstein Barr Virus, using a staining agent that can bind to the receptors on T cells that would be used to recognise and destroy the virus. There were more of these cells in the blood of MSers compared to people without MS. There were more in people with active MS. It is suggested that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation in the brain that can trigger relapse. Therefore more good reasons why we should attempt anti-viral therapy in MS.

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  • Where are we with the Charcot Project. I've seen no details of when it will start or how to apply to be a participant. I'd be grateful for some idea of the timeframe.

  • They have just started enrolling. I guess Prof G will make an update. The trial design on clinical trial. gov. NCT01767701 and time lines are there

  • Has the virus been quantified during active MS versus inactive disease by PCR? I assume CSF would be the specimen of choice. Have any studies in primates been performed using EBV as the trigger of disease?

    • Why Not…..

      Ethical Considerations.

      Nobody in the UK works of non-human primates for MS research (Thank the anti-vivs for that). Pharma may outsource work to some countries in Europe that do primate work…oh I forgot there are virtualy no pharma doing neuroscience work in UK.

      It takes time to produce animals for study and so the value of small studies are questionable.

      However you are right this colony of macaques (monkeys like the rhesus monkey) has a natural infection that causes demyelination.
      This would be useful to monitor this approach.

      I suspect it is cheaper to do the study in humans than it would be to do it in monkeys.

      Is this animal MS? They found the virusbyalot of hard work.

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