Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability
Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability
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DOI：
10.1002/ana.25666
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发表时间：
2020-01-27
影响因子：
11.2
通讯作者：
Schmitz, Dietmar
中科院分区：
文献类型：
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作者：
Kornau, Hans-Christian;Kreye, Jakob;Schmitz, Dietmar
目的富含亮氨酸的胶质瘤失活1（LGI 1）脑炎是第二常见的抗体介导的脑病，但对鞘内B细胞自身免疫反应的了解，包括克隆关系、同种型分布、频率和单个LGI 1抗体的致病作用，仍然有限。方法从90例LGI 1脑炎患者脑脊液（CSF）中分离抗体分泌细胞（ASCs）和B细胞，进行抗体的克隆、表达和检测。结果84%的ASCs和21%的记忆B细胞表达LGI 1反应性抗体，而对其他脑表位的反应性很少。所有LGI 1抗体均为IgG 1、IgG 2或IgG 4同种型，并已经历亲和力成熟。总共26种LGI 1抗体中有7种在体外有效地阻断了LGI 1与其受体ADAM 22的相互作用，与其余的非ADAM 22竞争性抗体相比，它们在小鼠脑切片上的平均LGI 1信号较弱。然而，这两种类型的LGI 1抗体增加了固有的细胞兴奋性和海马CA 3神经元的脑片培养物中的突触传递。解释我们的数据显示，患者的鞘内B细胞自身免疫反应由LGI 1抗体主导，并且单独的LGI 1抗体足以促进神经元兴奋性，这是癫痫发作的基础。与N-甲基-D-天冬氨酸受体脑炎的CSF自身抗体库相比，靶特异性和抗体超突变的根本差异强调了自身免疫性脑炎是非常不同的实体的临床概念。ANN NEUROL 2020
Objective 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. Methods 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. Results 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. Interpretation 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