7K7R

EBNA1 peptide AA386-405 with Fab MS39p2w174

Summary for 7K7R

• Entry DOI: 10.2210/pdb7k7r/pdb
• Descriptor: Fab LC MS39p2w174, Fab HC MS39p2w174, EBNA1 peptide AA386-405, ... (6 entities in total)
• Functional Keywords: autoantigen, ebv, antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 101025.90

Authors

Lanz, T.V.,Robinson, W.H.,Jude, K.M. (deposition date: 2020-09-23, release date: 2022-01-12, Last modification date: 2023-10-18)

Primary citation

Lanz, T.V.,Brewer, R.C.,Ho, P.P.,Moon, J.S.,Jude, K.M.,Fernandez, D.,Fernandes, R.A.,Gomez, A.M.,Nadj, G.S.,Bartley, C.M.,Schubert, R.D.,Hawes, I.A.,Vazquez, S.E.,Iyer, M.,Zuchero, J.B.,Teegen, B.,Dunn, J.E.,Lock, C.B.,Kipp, L.B.,Cotham, V.C.,Ueberheide, B.M.,Aftab, B.T.,Anderson, M.S.,DeRisi, J.L.,Wilson, M.R.,Bashford-Rogers, R.J.M.,Platten, M.,Garcia, K.C.,Steinman, L.,Robinson, W.H.
Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.
Nature, 603:321-327, 2022

PubMed 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 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.

PubMed: 35073561
DOI: 10.1038/s41586-022-04432-7

Experimental method

X-RAY DIFFRACTION (2.5 Å)