title: Association of innate immune activation with latent Epstein-Barr virus in active MS lesions.
abstract: OBJECTIVE
  To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.
  
  
  METHODS
  White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.
  
  
  RESULTS
  We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro.
  
  
  CONCLUSIONS
  These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.
authors.affiliation: Department of Neuropathology, John Radcliffe Hospital, University of Oxford, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Tzartos
authors.forename: G
authors.initials: G
authors.lastname: Khan
authors.forename: A
authors.initials: A
authors.lastname: Vossenkamper
authors.forename: M
authors.initials: M
authors.lastname: Cruz-Sadaba
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.forename: E
authors.initials: E
authors.lastname: Sefia
authors.forename: A
authors.initials: A
authors.lastname: Meager
authors.forename: A
authors.initials: A
authors.lastname: Elia
authors.forename: J M
authors.initials: JM
authors.lastname: Middeldorp
authors.forename: M
authors.initials: M
authors.lastname: Clemens
authors.forename: P J
authors.initials: PJ
authors.lastname: Farrell
authors.forename: G
authors.initials: G
authors.lastname: Giovannoni
authors.forename: U-C
authors.initials: UC
authors.lastname: Meier
mesh_terms: D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D016898:Interferon-alpha / Q000096:biosynthesis; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D014775:Virus Activation / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D016898:Interferon-alpha