High Levels of Epstein-Barr Virus Nuclear Antigen-1-Specific Antibodies and Infectious Mononucleosis Act Both Independently and Synergistically to Increase Multiple Sclerosis Risk.

Anna Karin Hedström,Jesse Huang,Julia Butt,Ingrid Kockum,Angelica Michel,Tim Waterboer,Tomas Olsson,Jan Hillert,Lars Alfredsson,Nicole Brenner

doi:10.3389/fneur.2019.01368

Abstract

Objective: Elevated levels of anti-EBNA-1 antibodies and infectious mononucleosis (IM) history have consistently been associated with multiple sclerosis (MS) risk. We aimed to study whether these aspects of Epstein–Barr virus (EBV) infection represent separate risk factors for MS and whether they both interact with MS-associated HLA genes in disease development.Methods: Two Swedish-population-based case–control studies were used, comprising 5,316 cases and 5,431 matched controls. Subjects with different HLA alleles, EBNA-1, and IM status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Causal mediation analysis was used to assess to what extent the relationship between IM history and MS risk was mediated by high anti-EBNA-1 antibody levels and vice versa.Results: The causal mediation analysis revealed that both aspects of EBV infection mainly act directly on MS risk. The direct effect of elevated anti-EBNA-1 antibody levels on MS risk, expressed on the OR scale, was 2.8 (95% CI 2.5–3.1), and the direct effect of IM history on MS risk was 1.7 (95% CI 1.5–2.0). A significant interaction between the two aspects of EBV infection was observed (RERI 1.2, 95% CI 0.3–2.0), accounting for about 50% of the total effect. Further, both aspects of EBV infection interacted with DRB1*15:01 and absence of A*02:01.Interpretation: Elevated anti-EBNA-1 antibody levels and IM history are different risk factors for MS. The two aspects of EBV infection act synergistically to increase MS risk, indicating that they partly are involved in the same biological pathways.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease in which the etiology involves both genetic and environmental factors
Using two population-based case–control studies, we aimed to study whether an altered antibody response to EBNA-1 antigens reflects a higher prevalence of infectious mononucleosis (IM) history among MS patients or whether elevated levels of anti-EBNA-1 antibodies and IM history represent separate risk factors
We studied the total threeway interaction between HLA-DRB1∗15:01, absence of HLAA∗02:01, and aspects of EBV infection (EBNA-1 status and IM, respectively) with regard to MS risk, comparing the joint effect of the three risk factors to the situation when each one acts separately

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease in which the etiology involves both genetic and environmental factors. High levels of anti-EBNA-1 antibodies, which may be a marker of a deficient response to EBV infection, have consistently been associated with increased MS risk [4]. Another consistent finding is the association between history of infectious mononucleosis (IM), indicative of post-childhood acquisition of EBV infection, and increased MS risk [5]. It is unknown whether high anti-EBNA-1 antibody levels and IM history represent separate risk factors for MS. No study has been powered enough to investigate the potential interaction between HLA genes and EBNA-1 status with regard to MS risk, taking IM history into consideration and vice versa

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Results

Conclusion