Journal
NATURE
Volume 603, Issue 7900, Pages 321-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04432-7
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Funding
- NIH [R01 AR063676, U19 AI110491, 1S10OD010582-01A1]
- Juvenile Diabetes Research Foundation
- Lupus Research Alliance Funding
- German Research Foundation (DFG) [LA3657/1, 406052676, PL-315/5-1]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH GIGMS [P30GM133894]
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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.
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.
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