Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians-Universität München, D-82152 Martinsried, Germany.
Department of Neurology, Institute of Translational Neurology, University of Münster, D-48149 Münster, Germany.
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9). doi: 10.1073/pnas.1916337118.
Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABA-R) is a rare form of autoimmune encephalitis. The pathogenesis is still unknown but autoimmune mechanisms were surmised. Here we identified a strongly expanded B cell clone in the cerebrospinal fluid of a patient with GABA-R encephalitis. We expressed the antibody produced by it and showed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry that it recognizes the GABA-R. Patch-clamp recordings revealed that it tones down inhibitory synaptic transmission and causes increased excitability of hippocampal CA1 pyramidal neurons. Thus, the antibody likely contributed to clinical disease symptoms. Hybridization to a protein array revealed the cross-reactive protein LIM-domain-only protein 5 (LMO5), which is related to cell-cycle regulation and tumor growth. We confirmed LMO5 recognition by immunoprecipitation and ELISA and showed that cerebrospinal fluid samples from two other patients with GABA-R encephalitis also recognized LMO5. This suggests that cross-reactivity between GABA-R and LMO5 is frequent in GABA-R encephalitis and supports the hypothesis of a paraneoplastic etiology.
抗神经元 γ-氨基丁酸 A 受体（GABA-R）抗体相关脑炎是一种罕见的自身免疫性脑炎。其发病机制尚不清楚，但推测与自身免疫机制有关。本研究在 1 例 GABA-R 脑炎患者的脑脊液中鉴定出一个强烈扩增的 B 细胞克隆。我们表达了由其产生的抗体，并通过酶联免疫吸附测定（ELISA）和免疫组织化学证实其识别 GABA-R。膜片钳记录显示，该抗体可抑制抑制性突触传递，并导致海马 CA1 锥体神经元兴奋性增加。因此，该抗体可能导致了临床疾病症状。与蛋白质芯片杂交显示，该抗体还识别具有细胞周期调节和肿瘤生长功能的 LIM 结构域只有 5 蛋白（LMO5）。我们通过免疫沉淀和 ELISA 验证了 LMO5 的识别，并显示另外 2 例 GABA-R 脑炎患者的脑脊液样本也识别 LMO5。这表明 GABA-R 和 LMO5 之间的交叉反应在 GABA-R 脑炎中很常见，并支持副肿瘤病因假说。
