Epstein-Barr virus and multiple sclerosis: interaction with HLA

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse

possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly

diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among

individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45–2.48% confidence interval (CI)), as

did raised EBNA1 IgG OR=1.74 (1.38–2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385–420 IgG levels were more strongly associated to MS than

total EBNA1 IgG, OR=3.60 (2.75–4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45–0.76 95%CI) and AP 0.39 (0.18–0.61 95%CI), respectively. The observed

interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part,

involve the immune control of EBV infection.

The study was supported by grants from the Swedish Association for Persons with Neurological Disabilities, The Swedish Research Council, The Söderbergs Foundation, the AFA foundation, the

Swedish Foundation for Working Life and Social research and the FP6 program Neuropromise (LSHM-CT-2005-018637). We thank Nina Nordin and Karin Kai-Larsen for help with collecting data.

Author contributions: ES did HLA genotyping and the statistical analysis, provided figures and wrote the paper. PS provided reagents and performed the anti-EBV antibody measurements. ML did

HLA genotyping. AKH collected clinical information on the EIMS participants. FA contributed to writing of the paper. IK supervised HLA genotyping and the statistical analysis. JH, LA and TO

are responsible for the EIMS study and the design of the study. All authors contributed to the final paper.

I Kockum, L Alfredsson and T Olsson: These authors contributed equally to this paper

Department of Clinical Neuroscience, Neuroimmunology Unit, Center for Molecular Medicine L8:05, Karolinska Institutet, Stockholm, Sweden

Department of Clinical Neuroscience, Umeå University, Umeå, Sweden

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy

Department of Clinical Neuroscience, Neurogenetics group, Center for Molecular Medicine L8:00, Karolinska Institutet, Stockholm, Sweden

Ms Sundqvist has received research support from the Swedish Association for Persons with Neurological Disabilities. Professor Hillert has received unrestricted research support from

BiogenIdec, MerckSerono and Bayer Schering. Professor Alfredsson receives research support from the Swedish Medical Research Council (Dnr 521-2009-2596) and Swedish Council for Working life

and Social Research (Dnr 2009-0650). Professor Tomas Olsson has received grant support for MS research from unrestricted grant support from BiogenIdec, Bayer, SanofiAventis and Merck, and

also lecture fees and/or advisory board consultancies for the same companies. Other authors declare no conflict of interest.

Supplementary Information accompanies the paper on Genes and Immunity website

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