Multiple sclerosis and Epstein-Barr virus.
BACKGROUND
Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear.


OBJECTIVE
To determine whether antibodies to EBV are elevated before the onset of MS.


METHODS
Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected.


METHODS
Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus.


RESULTS
The average time between blood collection and MS onset was 4 years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (> or =2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend =.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (< or =40). Similarly strong positive associations between EBV antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No association was found between cytomegalovirus antibodies and MS.


CONCLUSIONS
These results suggest a relationship between EBV infection and development of MS.
Levin
Lynn I
LI
Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC, USA.
Munger
Kassandra L
KL
Rubertone
Mark V
MV
Peck
Charles A
CA
Lennette
Evelyne T
ET
Spiegelman
Donna
D
Ascherio
Alberto
A
D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D000956:Antigens, Viral / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D016022:Case-Control Studies; D003587:Cytomegalovirus / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000503:physiopathology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology / Q000821:virology*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; C041788:Epstein-Barr viral capsid antigen; C033305:Epstein-Barr virus early antigen; C083204:Epstein-Barr virus early antigen diffuse component; D007070:Immunoglobulin A; D007074:Immunoglobulin G