Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study

JAMA. 2001 Dec 26;286(24):3083-8. doi: 10.1001/jama.286.24.3083.


Context: Epidemiological studies suggest an association between infection with Epstein-Barr virus (EBV) and risk of multiple sclerosis (MS).

Objective: To determine whether elevation in serum antibody titers to EBV viral capsid antigen (VCA), nuclear antigens (EBNA, EBNA-1, and EBNA-2), and diffuse and restricted early antigen (EA-D and EA-R) as well as to cytomegalovirus (CMV) precede the occurrence of MS.

Design, setting, and subjects: Prospective, nested case-control study. Of 62 439 women participating in the Nurses' Health Study (aged 30-55 years in 1976) and Nurses' Health Study II (aged 25-42 years in 1989) who gave blood samples in 1989-1990 and 1996-1999, respectively, and were followed up through 1999, 144 women with definite or probable MS and 288 healthy age-matched controls were included in the analysis.

Main outcome measure: Serum antibody titers to the specific EBV and CMV antigens, compared between cases and controls.

Results: We documented 18 cases of MS with blood collected before disease onset. Compared with their matched controls, these women had higher serum geometric mean titers (GMTs) of antibodies to EBV but not CMV. Elevations were significant for antibodies to EBNA-1 (GMT, 515 vs 203; P =.03), EBNA-2 (GMT, 91 vs 40; P =.01), and EA-D (15.9 vs 5.9; P =.04). The strongest association was found for antibodies to EBNA-2; a 4-fold difference in titers was associated with a relative risk (RR) of MS of 3.9 (95% confidence interval [CI], 1.1-13.7). The corresponding RRs were 1.6 (95% CI, 0.7-3.7) for VCA, 2.5 (95% CI, 1.0-6.3) for EBNA, 1.8 (95% CI, 1.0-3.1) for EA-D, and 1.0 (95% CI, 0.6-1.7) for CMV. Significant but generally weaker elevations in anti-EBV antibodies were also found in analyses of 126 cases of MS with blood collected after disease onset and their matched controls.

Conclusions: Our results support a role of EBV in the etiology of MS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antibodies, Viral / blood*
  • Antigens, Viral / immunology
  • Case-Control Studies
  • Cytomegalovirus / immunology
  • Cytomegalovirus Infections / complications
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Nuclear Antigens / immunology
  • Female
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Middle Aged
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / virology*
  • Prospective Studies
  • Risk Factors
  • Viral Proteins


  • Antibodies, Viral
  • Antigens, Viral
  • EBNA-2 protein, Human herpesvirus 4
  • Epstein-Barr Virus Nuclear Antigens
  • Epstein-Barr virus early antigen
  • Epstein-Barr virus early antigen diffuse component
  • Viral Proteins
  • EBV-encoded nuclear antigen 1