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

• Published in: Nature (London) Vol. 603; no. 7900; pp. 321 - 327
• Main Authors: Lanz, Tobias V., Brewer, R. Camille, Ho, Peggy P., Moon, Jae-Seung, Jude, Kevin M., Fernandez, Daniel, Fernandes, Ricardo A., Gomez, Alejandro M., Nadj, Gabriel-Stefan, Bartley, Christopher M., Schubert, Ryan D., Hawes, Isobel A., Vazquez, Sara E., Iyer, Manasi, Zuchero, J. Bradley, Teegen, Bianca, Dunn, Jeffrey E., Lock, Christopher B., Kipp, Lucas B., Cotham, Victoria C., Ueberheide, Beatrix M., Aftab, Blake T., Anderson, Mark S., DeRisi, Joseph L., Wilson, Michael R., Bashford-Rogers, Rachael J. M., Platten, Michael, Garcia, K. Christopher, Steinman, Lawrence, Robinson, William H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-03-2022; Nature Publishing Group
• Subjects: 45; 45/91; 631/250/2152/2497; 631/250/371; 631/250/38; 692/617/375/1666; 82; 82/58; Affinity; Animals; Antibodies; Antigens; Autoimmune diseases; B-Lymphocytes; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Adhesion Molecules, Neuron-Glia; Central nervous system; Cerebrospinal fluid; Crystal structure; Cytomegalovirus; DNA microarrays; Epidemiology; Epitopes; Epstein-Barr virus; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Flow cytometry; Glial cells; Herpesvirus 4, Human; Humanities and Social Sciences; Humans; Immunization; Immunoglobulins; In vivo methods and tests; Lymphocytes; Lymphocytes B; Measles; Mice; Mimicry; multidisciplinary; Multiple Sclerosis; Myelin; Nerve Tissue Proteins; Nervous system; Patients; Peptides; Post-translation; Protein arrays; Proteins; Science; Science (multidisciplinary); Sequence analysis; Sheaths; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04432-7

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.
The identification of high-affinity molecular mimicry between the Epstein–Barr virus (EBV) transcription factor EBNA1 and the CNS protein GlialCAM provides a mechanistic link between multiple sclerosis and EBV.