Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Department of Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Lancet. 2015 Feb 26;385 Suppl 1:S46. doi: 10.1016/S0140-6736(15)60361-0.
Leucine-rich glioma inactivated 1 (LGI1) is a component of the voltage-gated potassium channel complex. IgG antibodies against LGI1 are associated with immunotherapy-responsive encephalitis and epilepsies. LGI1-antibody concentrations are 10-100 times greater in serum than in cerebrospinal fluid (CSF). Oligoclonal IgG bands are rarely found in patients with LGI1-antibody encephalitis or epilepsy. These observations raise questions about the sources of the B cells that result in production of LGI1 antibodies and how the IgGs reach the brain. We aimed to investigate the migration and expansions of peripheral and central B cells to the production of LGI1-specific IgG.
We performed PCR amplification and next generation deep immune repertoire sequencing of immunoglobulin (Ig) heavy chain variable regions (VH) from CSF and subsorted peripheral blood B-cell populations from two patients with limbic encephalitis and faciobrachial dystonic seizures associated with LGI1 antibodies. Bioinformatics clustering of related IgM-VH or IgG-VH transcripts was used to determine whether active B-cell diversification could be observed, and whether intrathecal B-cell repertoires, if present, were related to peripheral B cells.
We identified clusters of related Ig-VH transcripts in the CSF of both patients. Within these clusters there was a range of somatic hypermutations along the IGHV germline segment-derived portion. In addition, we identified a large number of closely related Ig-VH clusters that were common to both CSF and peripheral blood, including a small number of dominating Ig-VH clusters that might represent the most active clonally related B-cell populations.
Our data suggest that some B-cell affinity maturation occurs inside the CNS compartment in LGI1-antibody encephalitis. Somatic hypermutation rates point to a CSF antigen-driven activation of clonally related B cells that shape the intrathecal immune repertoire. The target antigen or antigens of these clonally related B cells remain unknown; our work continues to determine the relative contribution of intrathecally activated and peripheral LGI1-specific B cells in this autoimmune CNS disease.
Wellcome Trust Intermediate Fellowship to SRI, Fulbright-MS Society, Epilepsy Research UK, BMA Vera Down Research Grant.
亮氨酸丰富的胶质瘤失活 1 型（LGI1）是电压门控钾通道复合物的组成部分。针对 LGI1 的 IgG 抗体与免疫治疗反应性脑炎和癫痫有关。LGI1 抗体在血清中的浓度是脑脊液（CSF）中的 10-100 倍。在患有 LGI1 抗体脑炎或癫痫的患者中，很少发现寡克隆 IgG 带。这些观察结果引发了关于导致 LGI1 抗体产生的 B 细胞来源以及 IgG 如何到达大脑的问题。我们旨在研究外周和中枢 B 细胞的迁移和扩增，以产生 LGI1 特异性 IgG。
我们对 2 例伴有 LGI1 抗体的边缘性脑炎和颜面臂肌张力障碍性发作患者的 CSF 和外周血 B 细胞亚群进行了免疫球蛋白（Ig）重链可变区（VH）的 PCR 扩增和下一代深度免疫受体测序。使用相关 IgM-VH 或 IgG-VH 转录本的生物信息学聚类来确定是否可以观察到活性 B 细胞多样化，以及如果存在鞘内 B 细胞受体谱，它们是否与外周 B 细胞相关。
我们在这 2 例患者的 CSF 中鉴定出了相关 Ig-VH 转录本的聚类。在这些聚类中，存在沿着 IGHV 胚系片段衍生部分的一系列体细胞高突变。此外，我们还鉴定出大量与 CSF 和外周血都相关的密切相关的 Ig-VH 聚类，包括少数占主导地位的 Ig-VH 聚类，这些聚类可能代表最活跃的克隆相关 B 细胞群体。
我们的数据表明，在 LGI1 抗体脑炎中，某些 B 细胞亲和力成熟发生在中枢神经系统（CNS）隔室内部。体细胞高突变率表明，CSF 中的抗原驱动了克隆相关 B 细胞的激活，从而形成了鞘内免疫受体谱。这些克隆相关 B 细胞的靶抗原或抗原尚不清楚；我们的工作继续确定在这种自身免疫性中枢神经系统疾病中，鞘内激活和外周 LGI1 特异性 B 细胞的相对贡献。
惠康中级研究员基金（SRI）、富布赖特-马萨诸塞州协会、英国癫痫研究协会、BMA 维拉唐研究赠款。
