From the Department of Neurology (K.L.-H., S.W., A.P., S.J., A.L.G., R.D., J.M.G., M.D.G., M.R.W., S.S.Z., H.-C.v.B.), UCSF Weill Institute for Neurosciences; Program in Immunology (K.L.-H., S.S.Z.), UCSF, San Francisco, CA; Department of Neurology (K.L.-H., G.L.), Klinikum rechts der Isar, Technische Universität München, Germany; and Oxford Autoimmune Neurology Group (S.R.I., S.M.), John Radcliffe Hospital, University of Oxford, UK.
Neurol Neuroimmunol Neuroinflamm. 2020 Feb 6;7(2). doi: 10.1212/NXI.0000000000000669. Print 2020 Mar.
To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.
Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.
Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.
Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.
研究富亮氨酸胶质瘤失活 1 型（LGI1）抗体脑炎中的鞘内 B 细胞活性。在 LGI1 抗体患者中，CSF 淋巴细胞增多或寡克隆带缺乏和血清优势 LGI1 抗体提示外周起始的免疫反应。然而，中枢神经系统内的 B 细胞是否有助于 LGI1 抗体脑炎的持续发病机制尚不清楚。
从 6 例 LGI1 抗体脑炎患者和 2 例其他神经疾病患者中收集配对的 CSF 和外周血（PB）单核细胞。对 CSF B 细胞和分选的 PB B 细胞亚群的免疫球蛋白重链转录物进行深度 B 细胞免疫受体库测序。此外，还测定了 CSF 和 PB 中的 LGI1 抗体水平。
血清 LGI1 抗体滴度平均比 CSF LGI1 抗体滴度高 127 倍。然而，深度 B 细胞受体库分析显示 CSF 受体库受限，频繁出现与成熟 PB B 细胞相连的克隆相关 B 细胞广泛集群。这些簇显示 CSF B 细胞强烈的突变活性，为 LGI1 抗体脑炎患者中存在独立于中枢神经系统的抗原驱动反应提供了有力证据，但在对照组中则没有。
我们的结果表明，鞘内免疫球蛋白受体库扩张是 LGI1 抗体脑炎的一个特征，并提示需要中枢神经系统渗透性治疗。
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