Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel

Mult Scler. 2011 Oct;17(10):1185-93. doi: 10.1177/1352458511408991. Epub 2011 Jun 17.


Background: Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized.

Objectives: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS.

Methods: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks.

Results: MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 × 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1.

Conclusions: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Viral / blood*
  • Area Under Curve
  • Biomarkers / blood*
  • Case-Control Studies
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Infections / epidemiology
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Nuclear Antigens / immunology
  • Female
  • Humans
  • Male
  • Military Personnel
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / virology*
  • Prospective Studies
  • ROC Curve
  • Radioimmunoassay
  • Risk Factors
  • United States
  • Vitamin D / blood
  • Young Adult


  • Antibodies, Viral
  • Biomarkers
  • Epstein-Barr Virus Nuclear Antigens
  • Vitamin D