Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis.
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. Serial samples collected before the onset of symptoms were available for 69 matched case-control sets.


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 (range, <1-11 years). The strongest predictors of MS were serum levels of IgG antibodies to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody titers to EBNA complex were similar to those of controls before the age of 20 years (geometric mean titers: cases = 245, controls = 265), but 2- to 3-fold higher at age 25 years and older (cases = 684, controls = 282; P<.001). The risk of MS increased with these antibody titers; the relative risk (RR) in persons with EBNA complex titers of at least 1280 compared with those with titers less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase in anti-EBNA complex or anti-EBNA-1 titers during the follow-up was associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0; 95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was found between cytomegalovirus antibodies and MS.


CONCLUSIONS
These results suggest an age-dependent relationship between EBV infection and development of MS.
Levin
Lynn I
LI
Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, Md, USA.
Munger
Kassandra L
KL
Rubertone
Mark V
MV
Peck
Charles A
CA
Lennette
Evelyne T
ET
Spiegelman
Donna
D
Ascherio
Alberto
A
D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D016022:Case-Control Studies; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000503:physiopathology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008889:Military Personnel; D009103:Multiple Sclerosis / Q000097:blood / Q000503:physiopathology / Q000821:virology*; D012307:Risk Factors; D014481:United States
D000914:Antibodies, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G