Accumulation and Ineffective Immune Control of Epstein-Barr Virus-Induced Cross-Reactive Immune Responses is associated with Multiple Sclerosis 9114

Abstract Description Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Epstein-Barr virus (EBV) encodes for the EBNA-1381-452 region that induces autoreactive immune responses with distinct CNS-derived proteins, which are likely critically involved in MS pathogenesis. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. We quantified EBNA-1381-452-specific antibody titers from 324 MS patients and 324 matched controls in longitudinal follow-up plasma samples, starting from the individual’s EBV-seroconversion. In MS patients, significantly elevated EBNA-1381-452-specific IgG titers were identified already as early as nine months after EBV-seroconversion (P < 0.0001) and a median 5.4 years prior to MS diagnosis. Continuous high-level EBNA-1381-452-specific antibody titers were associated with a more rapid MS diagnosis after EBV-seroconversion (P < 0.0001). Furthermore, MS patients were hallmarked by the accumulation of high-level cross-reactive EBNA-1381-452 and corresponding CNS-specific antibody, B-cell and T-cell responses that were associated with an up to 1366-fold increased risk for MS development. Functional analyzes revealed that MS patients exhibit a diminished ability to control the accumulation of autoreactive cells due to decreased control by cytotoxic NKG2C+ NK cell responses. Our findings provide further insights into pathogenesis and may allow the early identification of patients at risk for MS. Funding Sources The study was funded by the Center for Virology and the Department of Neurology, Medical University of Vienna, Vienna, Austria. H.V. received a research grant from the Austrian MS society. Topic Categories Viral Immunology (VIR)