Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM
Lanz TV., Brewer RC., Ho PP., Moon JS., Jude KM., Fernandez D., Fernandes RA., Gomez AM., Nadj GS., Bartley CM., Schubert RD., Hawes IA., Vazquez SE., Iyer M., Zuchero JB., Teegen B., Dunn JE., Lock CB., Kipp LB., Cotham VC., Ueberheide BM., Aftab BT., Anderson MS., DeRisi JL., Wilson MR., Bashford-Rogers RJM., Platten M., Garcia KC., Steinman L., Robinson WH.
Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein 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 allowed for tracking the development of the naïve 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 the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.