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What are T-cells telling us about how EBV causes MS?

Published:November 26, 2022DOI:https://doi.org/10.1016/j.msard.2022.104434
      As reviewed by others (
      • Robinson W.H.
      • Steinman L.
      Epstein-Barr virus and multiple sclerosis.
      ;
      • Sollid L.M.
      Epstein-Barr virus as a driver of multiple sclerosis.
      ;
      • Giovannoni G.
      • Vanderdonckt P.
      • Hartung H.-P.
      • Lassmann H.
      • Comi G.
      EBV and multiple sclerosis: Setting the research agenda.
      ;
      • Läderach F.
      • Münz C.
      Altered immune response to the epstein-barr virus as a prerequisite for multiple sclerosis.
      ;
      • Maple P.A.
      • Ascherio A.
      • Cohen J.I.
      • Cutter G.
      • Giovannoni G.
      • Shannon-Lowe C.
      • Tanasescu R.
      • Gran B.
      The Potential for EBV Vaccines to Prevent Multiple Sclerosis.
      ) and in our prior Editors' commentary (
      • Giovannoni G.
      • Hawkes C.H.
      • Lechner-Scott J.
      • Levy M.
      • Yeh E.A.
      • Gold J.
      Is EBV the cause of multiple sclerosis?.
      ), the evidence that EBV plays a pivotal role in the causal pathway that leads to MS is now overwhelming. Currently, there are two main competing theories of how EBV causes MS. On the one hand, is the ‘hit-and-run’ theory that EBV triggers autoimmunity through molecular mimicry, i.e. EBV fools the immune system into making an immune reaction against its proteins/antigens, in particular, EBV nuclear antigen-1 (EBNA-1), which then cross-reacts with antigens in the central nervous system (CNS) to cause focal inflammatory events that is MS (
      • Läderach F.
      • Münz C.
      Altered immune response to the epstein-barr virus as a prerequisite for multiple sclerosis.
      ). A second theory is that EBV is the ‘driver of MS’ by continually cycling through its latent and lytic infection phases is responsible for driving MS pathology (
      • Giovannoni G.
      • Vanderdonckt P.
      • Hartung H.-P.
      • Lassmann H.
      • Comi G.
      EBV and multiple sclerosis: Setting the research agenda.
      ). This could either be by (1) direct CNS infection, (2) continuously stimulating autoreactive T and B cells, or (3) upregulating a second virus such as MS-associated HERVs (human endogenous retroviruses or human herpes virus 6), which in turn cause tissue damage (
      • Küry P.
      • Nath A.
      • Créange A.
      • Dolei A.
      • Marche P.
      • Gold J.
      • Giovannoni G.
      • Hartung H.-P.
      • Perron H.
      Human endogenous retroviruses in neurological diseases.
      ). This latter is called the ‘dual-viral’ hypothesis of MS (
      • Giovannoni G.
      • Ebers G.
      Multiple sclerosis: the environment and causation.
      ).
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