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

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

Nature (London), 2022-03, Vol.603 (7900), p.321-327 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM
Autor: 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
Assuntos: 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 ; Humans ; Immunization ; Immunoglobulins ; In vivo methods and tests ; Lymphocytes ; Lymphocytes B ; Measles ; Mice ; Mimicry ; Multiple Sclerosis ; Myelin ; Nerve Tissue Proteins ; Nervous system ; Patients ; Peptides ; Post-translation ; Protein arrays ; Proteins ; Sequence analysis ; Sheaths ; Transcription factors ; Viruses
É parte de: Nature (London), 2022-03, Vol.603 (7900), p.321-327
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author contributions: Conceptualization, T.V.L., L.S., W.H.R.; Methodology, T.V.L., R.C.B., P.P.H., K.M.J., D.F., R.A.F., A.M.G., R.D.S., B.T., V.C.C., B.M.U., J.-S.M., M.I., J.B.Z.; Software, T.V.L., R.C.B., D.F., K.M.J., V.C.C.; Validation, T.V.L., R.C.B., K.M.J., B.M.U., R.J.M.B.-R., R.A.S., K.C.G., L.S., W.H.R., Formal Analysis, T.V.L., R.C.B., K.M.J., D.F., A.M.G., C.M.B., V.C.C., B.M.U.; Investigation, T.V.L., R.C.B., P.P.H., D.F., G.-S.N., C.M.B., R.D.S., I.A.H., S.E.V., B.T., V.C.C., J.-S.M., M.I.; Resources, T.V.L., P.P.H., D.F., B.T., J.E.D., C.B.L., L.B.K., B.M.U., M.R.W., M.S.A., J.L.D., M.P., R.A.S., K.C.G., L.S., W.H.R.; Data Curation, T.V.L., R.C.B., K.M.J., D.F., V.C.C., B.M.U.; Writing – Original Draft, T.V.L.; Writing – Review & Editing, T.V.L., R.C.B., P.P.H., L.S., W.H.R.; Visualization, T.V.L., R.C.B., K.M.J.; Supervision, T.V.L., W.H.R.; Project Administration, T.V.L., W.H.R.; Funding Acquisition, T.V.L., P.P.H., B.T.A., M.P., L.S., W.H.R.
Descrição: 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 . Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear . 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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