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多发性硬化症中克隆性扩增的B细胞与EBV EBNA1和GlialCAM结合
2022-01-30 23:12
来源：小柯机器人

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。

研究人员表示，多发性硬化症（MS）是一种异源性的自身免疫性疾病，其中自反应性淋巴细胞攻击中枢神经系统（CNS）的髓鞘。多发性硬化症患者脑脊液（CSF）中的B淋巴细胞促成了炎症，并分泌出寡克隆免疫球蛋白。爱泼斯坦-巴尔病毒（EBV）感染在流行病学上与多发性硬化症有关，但其病理作用仍不清楚。
 
研究人员证明了EB病毒转录因子EBNA1和中枢神经系统蛋白GlialCAM之间的高亲和性分子模拟，并为其相关性提供了结构和体内功能证据。通过对多发性硬化症血液和CSF的配对链B细胞的单细胞测序，研究人员最初确定了一种交叉反应的CSF衍生抗体，随后对重组表达的CSF衍生抗体进行了基于蛋白质芯片的测试来对抗MS相关病毒。序列分析、亲和力测量以及EBNA1肽表位与自体Fab片段复合物的晶体结构使研究人员能够追踪初始的EBNA1限制性抗体向成熟的EBNA1/GlialCAM交叉反应性抗体的发展。GlialCAM的翻译后修饰促进了分子模拟。EBNA1免疫会加剧多发性硬化症的小鼠模型，并且抗EBNA1/GlialCAM抗体在多发性硬化症患者中很普遍。这些研究结果为多发性硬化症和EB病毒之间的关联提供了一个机制上的联系，并可以指导新型多发性硬化症疗法的开发。
 
附：英文原文

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：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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