Elevated Epstein–Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis

Authors

  • Jan D. Lünemann MD,

    1. Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland
    2. Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY
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  • Mar Tintoré MD,

    1. Multiple Sclerosis Centre of Catalonia, CEM-Cat, Clinical Neuroimmunology Unit, Barcelona, Spain
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  • Brady Messmer BSc,

    1. Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland
    2. Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY
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  • Till Strowig PhD,

    1. Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland
    Current affiliation:
    1. Department of Immunobiology, Yale University, New Haven, CT
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  • Álex Rovira MD,

    1. Magnetic Resonance Unit (IDI), Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
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  • Héctor Perkal MD,

    1. Multiple Sclerosis Centre of Catalonia, CEM-Cat, Clinical Neuroimmunology Unit, Barcelona, Spain
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  • Estrella Caballero MD,

    1. Microbiology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
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  • Christian Münz PhD,

    1. Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland
    2. Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY
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  • Xavier Montalban MD,

    1. Multiple Sclerosis Centre of Catalonia, CEM-Cat, Clinical Neuroimmunology Unit, Barcelona, Spain
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  • Manuel Comabella MD

    Corresponding author
    1. Multiple Sclerosis Centre of Catalonia, CEM-Cat, Clinical Neuroimmunology Unit, Barcelona, Spain
    • Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain
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Abstract

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).

Interpretation

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. ANN NEUROL 2010;67:159–169

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