Single cell-based ultra high-resolution characterization of intrathecal immunity in Autoimmune Encephalitis

在这个建议中，我们的目标是研究免疫机制，它系统地保护我们免受感染和癌症，但在中枢神经系统(CNS)的背景下，可以引起炎症和针对神经元和突触的自身免疫。这种疾病被称为自身免疫性脑炎(AIE)，尽管很罕见，但越来越多地被认识到。它会导致渐进性记忆丧失、情绪紊乱和癫痫等。我们之前发现了一些可以预测疾病的标志物，但还没有对AIE的自身免疫进行全面的、无偏见的表征。利用先进的单细胞技术和分析，我们建议以极高的分辨率和精确度来表征AIE特有的细胞类型、标记、途径和基因。我们是一个独特而专注的临床医生和研究人员团队，治疗和研究大量的AIE患者，并管理着大型生物材料库，其中包括为我们的研究提供足够的患者材料。我们还开发和校准了新的基因组技术，以构建自身免疫性疾病中免疫细胞和途径的非常详细的模型。因此，我们的团队将尖端技术与稀有临床标本的获取以及在诊断这种异质性疾病方面的长期专业知识相结合。这将使我们能够更好地了解免疫细胞如何与发炎的大脑相互作用。世界领先的科学家和临床医生与新技术的杰出结合使我们特别有能力在AIE研究中开辟新的天地。我们认为，利用脑脊液的单细胞基因组分析，对局部免疫反应进行超高分辨率的表型分析，将为今后更好地了解、诊断、预测和治疗AIE提供基础。

In this proposal we aim to study the immune mechanisms, which systemically protect us from infections and cancer, but in the context of the central nervous system (CNS) can cause inflammation and auto-immunity against neurons and synapses. The disease condition is named autoimmune encephalitis (AIE) and – although rare – is increasingly being recognized. It can cause – among others – progressive memory loss, mood disturbances and seizures. We previously found a small number of markers that are predictive for the disease, but a full-scale unbiased characterization of autoimmunity in AIE has not been performed. Using advanced single cell technologies and analytics, we here propose to characterize the cell types, markers, pathways and genes that are specific to AIE with extremely high resolution and precision. We are a unique and focused group of clinicians and researchers treating and studying a large cohort of AIE patients and managing large biomaterial banks, which include sufficient patient material for our study. We have also developed and calibrated new genomic technologies to construct very detailed models of immune cells and pathways in autoimmune diseases. Our group thus combines cutting-edge technology with access to rare clinical specimen and a long-standing expertise in diagnosing this heterogeneous disorder. This will enable us to better understand how immune cells interact with the inflamed brain. This outstanding combination of world leading scientists and clinicians with new technologies makes us especially well equipped to break new grounds in AIE research. We propose that an ultra-high resolution phenotyping of local immune responses, using single cell genomic analysis of the CSF will provide a basis for better understanding, diagnosing, predicting and treating AIE in the future.