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

Author

Listed:
  • Tobias V. Lanz

    (Stanford University School of Medicine
    University of Heidelberg
    University Hospital Heidelberg
    VA Palo Alto Health Care System)

  • R. Camille Brewer

    (Stanford University School of Medicine
    VA Palo Alto Health Care System)

  • Peggy P. Ho

    (Stanford University School of Medicine, Beckman Center for Molecular Medicine)

  • Jae-Seung Moon

    (Stanford University School of Medicine
    VA Palo Alto Health Care System)

  • 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
    VA Palo Alto Health Care System)

  • Gabriel-Stefan Nadj

    (Stanford University School of Medicine
    VA Palo Alto Health Care System)

  • 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
    NYU School of Medicine)

  • Beatrix M. Ueberheide

    (NYU Perlmutter Cancer Center, NYU School of Medicine
    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
    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
    University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • 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
    VA Palo Alto Health Care System)

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.

Suggested Citation

  • 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, 2022. "Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM," Nature, Nature, vol. 603(7900), pages 321-327, March.
  • Handle: RePEc:nat:nature:v:603:y:2022:i:7900:d:10.1038_s41586-022-04432-7
    DOI: 10.1038/s41586-022-04432-7
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    Citations

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    Cited by:

    1. Grant Broussard & Guoxin Ni & Zhigang Zhang & Qian Li & Patricio Cano & Dirk P. Dittmer & Blossom Damania, 2023. "Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Vijayendra Dasari & Lisa K. McNeil & Kirrilee Beckett & Matthew Solomon & George Ambalathingal & T. Le Thuy & Archana Panikkar & Caitlyn Smith & Martin P. Steinbuck & Aniela Jakubowski & Lochana M. Se, 2023. "Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Anthony C. Ebert & Shania Harper & Marie V. Vestergaard & Wayne Mitchell & Tine Jess & Rahma Elmahdi, 2024. "Risk of inflammatory bowel disease following hospitalisation with infectious mononucleosis: nationwide cohort study from Denmark," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Cole Maguire & Chumeng Wang & Akshara Ramasamy & Cara Fonken & Brinkley Morse & Nathan Lopez & Dennis Wylie & Esther Melamed, 2024. "Molecular mimicry as a mechanism of viral immune evasion and autoimmunity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Garrett Dunlap & Aaron Wagner & Nida Meednu & Ruoqiao Wang & Fan Zhang & Jabea Cyril Ekabe & Anna Helena Jonsson & Kevin Wei & Saori Sakaue & Aparna Nathan & Vivian P. Bykerk & Laura T. Donlin & Susan, 2024. "Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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