EBV and multiple sclerosis: Setting the research agenda

Published:September 05, 2022DOI:
      The European Charcot Foundation in relation to its Mystery Solved Project hosted an online meeting, from the 5th to the 8th July 2022, to explore recent and related evidence that multiple sclerosis (MS) may be caused by Epstein Barr virus (EBV) (see Table 1 for the meeting programme).
      Table 1Mystery Solved Project EBV and multiple sclerosis online meeting.
      Date Theme, lectures and discussants Participants
      Day 1

      Epidemiology and pathology
      Introduction Patrick Vanderdonckt (Kortrijk, Belgium) & Giancarlo Comi (Milan, Italy)
      Lecture 1 Causation theory and how it applies to EBV as a cause of MS

      What more needs to be done to prove EBV is the cause of MS? What is the definitive experiment then?
      Alberto Ascherio (Cambridge; USA)
      The epidemiology of MS and EBV

      How does EBV explain the epidemiology of MS, i.e. increasing incidence, increasing female:male sex ratio,altitudinal gradient, etc.?

      Potential mechanisms of how EBV interacts with other environmental risk factors to cause MS?

      What further studies are required to establish how EBV interacts with other risk factors?
      Ingrid Kockum (Stockholm, Sweden)
      The genetics of MS and how they interact with EBV

      How does EBV interact with the MS-transcriptome?

      What needs to be done to explore the genomics of EBV and MS?
      Phil De Jager (New York, USA)
      Invited discussant - EBV and MS Marco Salvetti (Rome, Italy)
      Q&A / Discussion at the end of day 1 Giancarlo Comi (Milan, Italy) & Gavin Giovannoni (London, UK)
      Day 2.1 6-July-2022 Pathology and the immunopathology of MS
      EBV and the pathology of MS and related disorders

      What is MS in relation to other inflammatory demyelinating diseases?

      What is the key mechanism, which drives chronic (progressive) pathology; is this the aspect which differentiates MS from other acute monophasic or relapsing inflammatory demyelination diseases (such as MOGAD)?
      Hans Lassmann (Vienna, Austria)
      EBV as a driver of MS disease activity

      What is the evidence against the hit-and-run hypothesis? In which compartment is EBV driving MS disease activity?

      Regarding detection of EBV in brain tissue; is it pathogenic, a bystander phenomenon or an artefact?
      Francesca Aloisi (Rome, Italy)
      EBV and MRI

      Does MRI activity correlate with EBV biology?

      How do you explain end-organ damage markers in relation to EBV?
      Robert Zivadinov (Buffalo, USA)
      Day 2.2 6-July-2022 Animal models of EBV infection and MS
      How good are humanised mice at representing EBV infection in relation to MS

      How good are humanised mice at recapitulating human immunology?

      Can mice be used to define the role of the MHC in MS?

      Can human mice be used to develop and test new MS treatments?
      Christian Münz (Zürich, Switzerland)
      What can we learn from rabbit model of EBV

      What can we learn about a spontaneous CNS infection model of EBV?

      What is the relevance of primary CNS infection with EBV to MS?

      Can this animal model be used to develop treatment for MS?
      Gulfaraz Khan (Al Ain, UAE)
      Is Japanese macaque encephalomyelitis (JME) animal MS?

      How closely does the pathology and imaging features of JME mimic MS?

      What are the differences between CIS and acute JME and MS?

      Does JME responde to MS DMTs?
      Dennis Bourdette (Portland, Oregon)
      Q&A / Discussion at the end of day 2 Hans Lassmann (Vienna, Austria) & Gavin Giovannoni (London, UK)
      Day 3 - 7-July-2022 Immunopathology of MS
      EBNA-1 and MS

      What is the biology of EBNA-1 and how does its biology differ in people with MS?

      How to target EBNA-1 as a potential target to treat MS?
      Lawrence Young (Warwick, UK)
      EBNA2 and the B-cell

      EBNA-2 and its effect on B-cell biology

      How is this relevant to MS and autoimmunity in general?
      Matt Weirauch (Cincinnati, USA)
      Molecular mimicry, EBV and MS

      What is the case for EBV molecular mimicry in the pathogenesis of MS?

      What is the MS autoantigen?

      Targeting molecular mimicry as a treatment option in MS?
      Ivan Jelcic (Basel, Switzerland)
      T-cell therapy and related issues

      What lessons can be learnt from infectious mononucleosis

      Can we use EBV-specific T-cell therapies to treat MS?
      Rajiv Khanna (Brisbane, Australia)
      The immunology of MS and how it interacts with EBV

      Can latent EBV infection of B-cells explain the aberrant B-cell biology in MS?

      What further experiments need to be done to test the EBV-B-cell hypothesis?
      Jan Lünemann (Münster, Germany)
      Memory B-cells and MS

      What is the evidence that the memory B-cell is the primary driver of MS disease activity?

      Could this be explained by latent EBV infection?
      Joseph Berger (Philadelphia, USA)
      EBV and the MS B-cell repertoire

      Is EBV involved in the generation of the oligoclonal IgG response?

      What have we learnt about the immunoglobulin repertoire in MS?

      What needs to be done to further explore the link between EBV and the intrathecal oligoclonal IgG?
      William Robinson (Stanford, USA)
      Q&A / Discussion at the end of day 3 Hans-Peter Hartung (Dusseldorf, Germany) & Gavin Giovannoni (London, UK)
      Day 4 - 8-July-2022 The viral hypothesis of MS
      The dual viral hypothesis of MS

      Is EBV working via human endogenous retroviruses?

      What about the negative association between HIV and MS; is due to HERVs?
      Zsolt Illes (Odense, Denmark)
      Treating MS with antivirals

      What is the evidence that antivirals work in MS?

      What trials are needed to test the viral hypothesis of MS?
      Julian Gold (Sydney, Australia)
      EBV the virus

      The genetic evolution of EBV

      Can diversity in the EBV genome potentially explain the EBV-MS association?

      What hypotheses need testing and what experiments need to be done?
      Judith Breuer (London, UK)
      Infectious mononucleosis and MS

      The changing epidemiology of IM

      How can we target IM as a possible preventive strategy for MS?
      Henry Balfour (Minnesota, USA)
      How to design an EBV vaccine experiment to prove EBV causes MS

      Does the EBV vaccine need to result in sterilising immunity?

      How long does the trial have to be?

      Can you design a shorter experiment?

      What happens if the EBV vaccine trial doesn't work?
      Gavin Giovannoni (London, UK)
      EBV vaccines

      EBV vaccine update

      How far are we from MS prevention studies?
      Jeff Cohen (NIH Bethesda, USA)
      Power calculations for EBV vaccine prevention studies

      How big do the studies need to be?

      What is the target population?

      Can we use an intermediate phenotype as a primary outcome measure?
      Gary Cutter (Birmingham, Alabama; USA)
      Administrative health records as a tool to explore the EBV-MS hypothesis

      What can be done with administrative health records to explore the MS EBV hypothesis?

      What resources are required to do this work?
      Ruth Ann-Marrie (Manitoba, Canada)
      Q&A / Discussion at the end of day 4 Gavin Giovannoni (London, UK) & Hans-Peter Hartung (Dusseldorf, Germany)
      Open discussion and conclusions and next steps Gavin Giovannoni, Hans Lassman, Giancarlo Comi & Patrick Vanderdonckt
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