Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins(1,2). Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear(3). Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Automated summary

Multiple sclerosis (MS) is an autoimmune disease where autoreactive lymphocytes attack the central nervous system. Epstein-Barr virus (EBV) infection has been linked to MS, with molecular mimicry between EBV nuclear antigen 1 (EBNA1) and central nervous system protein GlialCAM. EBNA1 immunization exacerbates disease in MS mouse models and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in MS patients, providing a mechanistic link between MS and EBV and guiding the development of new MS therapies.