Assistant Professor of Immunology Stanford University Stanford, California, United States
Abstract Text: Infection with Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), but the molecular mechanisms that explain this connection remain incompletely understood. Here we identified a cross-reactive antibody that binds the EBV transcription factor EBNA1 and the glial cellular adhesion molecule GlialCAM with high affinity, and we propose this molecular mimicry to be a mechanistic link that connects EBV and MS on a molecular level. The identified antibody binds EBV EBNA1 at an epitope known to elicit high antibody reactivity in MS patients. We provide structural evidence for the evolution from an unmutated B cell binding only EBNA1 to a cross-reactive antibody that also binds GlialCAM. Cross-reactivity is facilitated by a post-translational modification of GlialCAM. EBNA1-GlialCAM cross-reactive antibodies are more prevalent in MS patients than in healthy controls. Functional evidence for the impact of EBNA1/GlialCAM molecular mimicry was obtained from EBNA1-immunizations of the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Anti-viral antibodies in the CSF of MS patients were identified by single-cell B cell repertoire sequencing, followed by recombinant expression of selected clonally expanded antibody sequences. Antibodies were tested against a spectrum of viruses implicated in MS pathogenesis using protein microarrays. Binding and high affinity were confirmed by ELISA and biolayer-interferometry. Structures of antigen-antibody complexes were solved with X-ray crystallography. EAE mice were immunized with EBNA1 to investigate its effect in-vivo. Our results suggest that molecular mimicry between EBNA1 and GlialCAM is a relevant pathomechanism and provides a long sought mechanistic link for the association between MS and EBV.
