美国斯坦福大学医学院William H. Robinson研究小组发现,多发性硬化症中克隆性扩增的B细胞与EBV EBNA1和GlialCAM结合。2022年1月24日,《自然》杂志在线发表了这项成果。
Title: Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM
Author: 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.
Issue&Volume: 2022-01-24
Abstract: Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein 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 allowed for tracking the development of the naïve 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 the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.
DOI: 10.1038/s41586-022-04432-7
Source: https://www.nature.com/articles/s41586-022-04432-7
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html