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

Tobias V. Lanz, R. Camille Brewer, Peggy P. Ho, Jae-Seung Moon, Kevin M. Jude, Daniel Fernandez, Ricardo A. Fernandes, Alejandro M. Gomez, Gabriel-Stefan Nadj, Christopher M. Bartley, Ryan D. Schubert, Isobel A. Hawes, Sara E. Vazquez, Manasi Iyer, J. Bradley Zuchero, Bianca Teegen, Jeffrey E. Dunn, Christopher B. Lock, Lucas B. Kipp, Victoria C. Cotham, Beatrix M. Ueberheide, Blake T. Aftab, Mark S. Anderson, Joseph L. DeRisi, Michael R. Wilson, Rachael J. M. Bashford-Rogers, Michael Platten, K. Christopher Garcia, Lawrence Steinman and William H. Robinson ()
Additional contact information
Tobias V. Lanz: Stanford University School of Medicine
R. Camille Brewer: Stanford University School of Medicine
Peggy P. Ho: Stanford University School of Medicine, Beckman Center for Molecular Medicine
Jae-Seung Moon: Stanford University School of Medicine
Kevin M. Jude: Stanford University School of Medicine, Beckman Center for Molecular Medicine
Daniel Fernandez: Stanford ChEM-H Institute
Ricardo A. Fernandes: Stanford University School of Medicine, Beckman Center for Molecular Medicine
Alejandro M. Gomez: Stanford University School of Medicine
Gabriel-Stefan Nadj: Stanford University School of Medicine
Christopher M. Bartley: University of California San Francisco
Ryan D. Schubert: University of California San Francisco
Isobel A. Hawes: University of California San Francisco
Sara E. Vazquez: University of California San Francisco
Manasi Iyer: Stanford University School of Medicine
J. Bradley Zuchero: Stanford University School of Medicine
Bianca Teegen: Institute of Experimental Immunology, Euroimmun AG
Jeffrey E. Dunn: Stanford University School of Medicine
Christopher B. Lock: Stanford University School of Medicine
Lucas B. Kipp: Stanford University School of Medicine
Victoria C. Cotham: NYU Perlmutter Cancer Center, NYU School of Medicine
Beatrix M. Ueberheide: NYU Perlmutter Cancer Center, NYU School of Medicine
Blake T. Aftab: Atara Biotherapeutics
Mark S. Anderson: University of California San Francisco
Joseph L. DeRisi: University of California San Francisco
Michael R. Wilson: University of California San Francisco
Rachael J. M. Bashford-Rogers: University of Oxford
Michael Platten: University of Heidelberg
K. Christopher Garcia: Stanford University School of Medicine, Beckman Center for Molecular Medicine
Lawrence Steinman: Stanford University School of Medicine, Beckman Center for Molecular Medicine
William H. Robinson: Stanford University School of Medicine

Nature, 2022, vol. 603, issue 7900, 321-327

Abstract: Abstract 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 immunoglobulins1,2. Epstein–Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04432-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:603:y:2022:i:7900:d:10.1038_s41586-022-04432-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04432-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().