title: Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI.
abstract: BACKGROUND
  Evidence suggests that Epstein-Barr virus (EBV) plays a role in triggering or perpetuating disease activity in multiple sclerosis (MS).
  
  
  METHODS
  We investigated 100 subjects (50 clinically isolated syndrome [CIS], 25 relapsing-remitting [RR] MS, 25 primary progressive [PP] MS) for 1) evidence of EBV reactivation and 2) disease activity as indicated by serial gadolinium (Gd)-enhanced MRIs over a 5-year period. EBV DNA in blood was quantified by real-time quantitative PCR and EBV serology for anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG), anti-viral capsid antigen (VCA) IgG, and anti-EBV IgM. Data were analyzed using repeated measures analysis, analysis of variance, and logistic regression analysis.
  
  
  RESULTS
  All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035).
  
  
  CONCLUSIONS
  The correlation between elevated Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) and gadolinium-enhancing lesions suggests an association between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) disease activity. The heightened immune response to EBV in MS is specifically related to EBNA-1 IgG, a marker of the latent phase of the virus. The lack of association between acute viral reactivation in the peripheral blood and Gd(+) lesions suggests a limited role of the former in driving disease activity.
authors.affiliation: Department of Neuroinflammation, Institute of Neurology, UCL, Queen Square, London, UK. r.farrell@ion.ucl.ac.uk
authors.forename: R A
authors.initials: RA
authors.lastname: Farrell
authors.forename: D
authors.initials: D
authors.lastname: Antony
authors.forename: G R
authors.initials: GR
authors.lastname: Wall
authors.forename: D A
authors.initials: DA
authors.lastname: Clark
authors.forename: L
authors.initials: L
authors.lastname: Fisniku
authors.forename: J
authors.initials: J
authors.lastname: Swanton
authors.forename: Z
authors.initials: Z
authors.lastname: Khaleeli
authors.forename: K
authors.initials: K
authors.lastname: Schmierer
authors.forename: D H
authors.initials: DH
authors.lastname: Miller
authors.forename: G
authors.initials: G
authors.lastname: Giovannoni
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000032:analysis / Q000097:blood; D000917:Antibody Formation / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D015331:Cohort Studies; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood; D007075:Immunoglobulin M / Q000032:analysis / Q000097:blood; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000503:physiopathology / Q000821:virology*; D011237:Predictive Value of Tests; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D004279:DNA, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; C041788:Epstein-Barr viral capsid antigen; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C417029:EBV-encoded nuclear antigen 1