Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis.
OBJECTIVE
The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CISs), and to evaluate their potential value in predicting conversion to MS.


METHODS
Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.


RESULTS
Compared with controls, CIS patients showed increased humoral (p < 0.0001) and cellular (p = 0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins. Immunoglobulin G (IgG) responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen with which immune responses correlated with number of T2 lesions (p = 0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p = 0.012 at both 1 and 5 years), presence of new T2 lesions (p = 0.003 and p = 0.028 at 1 and 5 years), and Expanded Disability Status Scale score (p = 0.015 and p = 0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria (hazard ratio [95% confidence interval], 2.2 [1.2-4.3]; p = 0.003).


CONCLUSIONS
Our results indicate that elevated immune responses toward EBNA1 are selectively increased in CIS patients and suggest that EBNA1-specific IgG titers could be used as a prognostic marker for disease conversion and disability progression.
Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland.
Jan D
JD
Lünemann
Mar
M
Tintoré
Brady
B
Messmer
Till
T
Strowig
Alex
A
Rovira
Héctor
H
Perkal
Estrella
E
Caballero
Christian
C
Münz
Xavier
X
Montalban
Manuel
M
Comabella
D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D004185:Disability Evaluation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013223:Statistics as Topic; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D013997:Time Factors; D055815:Young Adult
D000914:Antibodies, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D007371:Interferon-gamma