title: Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins.
abstract: 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.
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands/Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Gijsbert P
authors.initials: GP
authors.lastname: van Nierop
authors.affiliation: Helmholtz Zentrum München and Technical University, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Mautner
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands/Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Mitterreiter
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands/Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany g.verjans@erasmusmc.nl.
authors.forename: Georges M G M
authors.initials: GM
authors.lastname: Verjans
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D014764:Viral Proteins / Q000276:immunology*; D038203:alpha-Crystallin B Chain / Q000276:immunology
chemical_list: D001324:Autoantigens; C059215:CRYAB protein, human; D014764:Viral Proteins; D038203:alpha-Crystallin B Chain
keywords: Autoantibodies; Epstein-Barr virus; T-cells; cerebrospinal fluid; clinically-isolated syndrome; crystallin; disease control; herpesviridae; intrathecal space; lytic antigen; multiple sclerosis; target antigen