Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis
Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis
复制标题
DOI：
10.1093/brain/aww208
复制
发表时间：
2016-10-01
期刊：
影响因子：
14.5
通讯作者：
Pruss, Harald
中科院分区：
文献类型：
--
作者：
Kreye, Jakob;Wenke, Nina K.;Pruss, Harald
针对NMDA受体NR 1亚单位的抗体被怀疑是抗NMDA受体脑炎的基础。Kreye等人通过显示单克隆人NR 1抗体足以下调突触NMDA受体提供了直接证据。他们还表明，患者体内的自身抗体库比以前想象的要广泛得多。参见Zekeridou和Lennon（doi：related-article ext-link-type=“doi”id=“RA 3”related-article-type=“companion”xlink：href=“10.1093/brain/aww 213“10.1093/aww 213 related-article）对这篇文章的科学评论。针对NMDA受体NR 1亚基的抗体被怀疑是抗NMDA受体脑炎的基础。Kreye等人通过显示单克隆人NR 1抗体足以下调突触NMDA受体提供了直接证据。抗N-甲基-D-天冬氨酸受体（NMDAR）脑炎是最近发现的与精神病、运动障碍和癫痫发作相关的自身免疫综合征。对脑脊液自身抗体库知之甚少。针对NMDAR的NR 1亚基的抗体被认为是致病性的;然而，由于先前的实验无法区分进一步的抗神经元抗体的贡献，因此缺乏直接证据。使用全长免疫球蛋白重链和轻链基因的单细胞克隆，我们从NMDAR脑炎患者的脑脊液记忆B细胞和抗体分泌细胞中产生了一组重组单克隆NR 1抗体。细胞通常携带体细胞突变的免疫球蛋白基因，并经历了类转换为免疫球蛋白G，克隆扩增的细胞携带相同的体细胞超突变模式。一部分NR 1抗体是非突变的，因此类似于“天然存在的抗体”，并表明针对NMDAR的耐受性诱导是不完全的，并且体细胞超突变对于功能性抗体不是必需的。然而，只有一小部分脑脊液来源的抗体对NR 1反应。相反，几乎所有进一步的抗体特异性结合到不同的脑表达表位，包括神经元表面，这表明在脑炎期间，广泛的抗体分泌细胞库在中枢神经系统中富集。我们使用原代海马神经元的功能数据表明，人脑脊液衍生的单克隆NR 1抗体单独足以引起神经元表面受体下调和随后的NMDAR介导的电流损伤，从而提供了抗体致病性的最终证据。所观察到的免疫记忆的形成可能与临床复发有关。
Antibodies against the NR1 subunit of the NMDA receptor are suspected to underlie anti-NMDA receptor encephalitis. Kreye et al. provide direct evidence by showing that monoclonal human NR1 antibodies are sufficient to downregulate synaptic NMDA receptors. They show too that patients harbour a much broader auto-antibody repertoire than previously thought.See Zekeridou and Lennon (doi:related-article ext-link-type="doi" id="RA3" related-article-type="companion" xlink:href="10.1093/brain/aww213"10.1093/aww213related-article) for a scientific commentary on this article.Antibodies against the NR1 subunit of the NMDA receptor are suspected to underlie anti-NMDA receptor encephalitis. Kreye et al. provide direct evidence by showing that monoclonal human NR1 antibodies are sufficient to downregulate synaptic NMDA receptors. They show too that patients harbour a much broader auto-antibody repertoire than previously thought.Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.