German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
Neuroscience Research Center, Cluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Ann Neurol. 2020 Mar;87(3):405-418. doi: 10.1002/ana.25666. Epub 2020 Jan 27.
Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited.
We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis.
Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures.
Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.
富含亮氨酸胶质瘤失活 1 蛋白（LGI1）脑炎是第二种最常见的抗体介导性脑病，但对于鞘内 B 细胞自身免疫反应，包括克隆关系、同种型分布、频率以及单个 LGI1 抗体的致病作用，人们的认识仍然有限。
我们从数名 LGI1 脑炎患者的脑脊液中克隆、表达并测试了 90 个抗体分泌细胞（ASC）和 B 细胞的抗体。
84%的 ASC 和 21%的记忆 B 细胞编码 LGI1 反应性抗体，而针对其他脑表位的反应性抗体则很少见。所有的 LGI1 抗体均为 IgG1、IgG2 或 IgG4 同种型，并经历了亲和力成熟。在总共 26 个 LGI1 抗体中，有 7 个抗体能够有效地阻断 LGI1 与其受体 ADAM22 之间的体外相互作用，与其余不与 ADAM22 竞争的抗体相比，它们在小鼠脑切片上的 LGI1 信号平均较弱。然而，这两种类型的 LGI1 抗体都增加了海马 CA3 神经元在切片培养物中的固有细胞兴奋性和谷氨酸能突触传递。
我们的数据表明，患者的鞘内 B 细胞自身免疫反应主要由 LGI1 抗体主导，并且单独的 LGI1 抗体就足以促进神经元兴奋性，这是癫痫发作产生的基础。与 N-甲基-D-天冬氨酸受体脑炎中的 CSF 自身抗体库相比，在靶特异性和抗体超突变方面存在根本差异，这突出了自身免疫性脑炎是非常不同的实体这一临床概念。神经病学年鉴 2020；87：405-418。
