Mapping T cell antigen-specificity in LGI1 antibody encephalitis

绘制 LGI1 抗体脑炎中 T 细胞抗原特异性图谱

• 批准号: MR/X022013/1
• 负责人: Adam Handel
• 金额: $ 97.5万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX022013%2F1
• 关键词: Mapping; cell; antigen; specificity; LGI1

BackgroundAutoimmune encephalitis refers to brain inflammation due to a misdirected immune response. This condition causes many symptoms including memory loss, seizures and psychiatric issues. Autoantibodies against Leucine Rich Glioma Inactivated 1 (LGI1) cause LGI1 antibody encephalitis, the commonest type of autoimmune encephalitis. Although steroids and other immune therapies are available, patients with LGI1 antibody encephalitis suffer long-term problems with mood, memory and fatigue despite current best treatments.Although B cells produce LGI1 autoantibodies, there is strong evidence that T cells are also important in LGI1 antibody encephalitis. T cells are immune cells that use T cell receptors to recognise particular small sections of proteins called peptides and then generate an immune response either directly or through activating other immune cell types. T cells provide an effective defence against infections and tumours but can cause autoimmunity when they react to peptides naturally present in the body.T cells develop in an organ called the thymus, in which T cells recognising self-peptides are eliminated through a process called negative selection. However, negative selection is imperfect and can result in self-reactive T cells being present in the blood and other parts of the body.I aim to study LGI1-reactive T cells in LGI1 antibody encephalitis throughout the entire development of T cells: from their initial production in the thymus, to their initial reaction against LGI1 peptides in peripheral blood, and to their eventual inflammatory response within cerebrospinal fluid (CSF) surrounding the brain.This project will comprehensively understand how T cells target LGI1 peptides in LGI1 antibody encephalitis, and ultimately lead to the development of new LGI1-specific T cell-targeted treatments.ApproachI will use small peptides generated by splitting the LGI1 protein into small fragments to activate T cells from the peripheral blood of patients with LGI1 antibody encephalitis. This will identify which LGI1 peptides underlie the T cell responses in this condition. These peptides can then be loaded into antigen-presenting molecules and used to isolate LGI1-reactive T cells from peripheral blood.I will then take advantage of innovative single cell sequencing technologies, which allow me to measure the expression level of every gene in an individual cell, along with sequencing its T cell receptor sequence. This method will be used to study LGI1-reactive developing T cells in the thymus, and also in the peripheral blood and CSF from patients with LGI1 antibody encephalitis and control subjects.In parallel, I will use a method called CODEX on thymus samples. This method allows me to examine the abundance and distribution of many proteins simultaneously. I will use this to understand how LGI1 peptides are presented to developing T cells and thus how self-reactive T cells may escape negative selection into the peripheral blood.ImpactThis project will identify how LGI1-reactive T cells escape negative selection in the thymus. I will also show what subtype of T cells react to LGI1 peptides in patients with LGI1 antibody encephalitis and understand how this can result in brain inflammation. This is likely to uncover novel mechanisms underlying LGI1 antibody encephalitis that will lead to targeted treatment measures directed at specifically suppressing LGI1-reactive T cells while leaving other T cells unaffected. These results will also be important in understanding the role of T cells in other neuroimmunological diseases, and T cell peptide-reactivity in autoimmune diseases more widely, in cancer and in infectious diseases.

背景自身免疫性脑炎是指由于免疫反应错误而导致的脑部炎症。这种情况会导致许多症状，包括记忆丧失、癫痫发作和精神问题。针对富含亮氨酸的胶质瘤失活 1 (LGI1) 的自身抗体会导致 LGI1 抗体脑炎，这是最常见的自身免疫性脑炎类型。尽管可以使用类固醇和其他免疫疗法，但 LGI1 抗体脑炎患者尽管采用了目前最好的治疗方法，仍长期遭受情绪、记忆和疲劳问题。虽然 B 细胞产生 LGI1 自身抗体，但有强有力的证据表明，T 细胞在 LGI1 抗体中也很重要脑炎。 T 细胞是免疫细胞，使用 T 细胞受体识别称为肽的蛋白质的特定小部分，然后直接或通过激活其他免疫细胞类型产生免疫反应。 T 细胞可以有效防御感染和肿瘤，但当它们与体内天然存在的肽发生反应时，可能会引起自身免疫。T 细胞在称为胸腺的器官中发育，在胸腺中，识别自身肽的 T 细胞通过称为负性的过程被消除选择。然而，阴性选择并不完美，可能会导致血液和身体其他部位出现自身反应性 T 细胞。我的目标是在 T 细胞的整个发育过程中研究 LGI1 抗体脑炎中的 LGI1 反应性 T 细胞：胸腺中的初始产生，对外周血中 LGI1 肽的初始反应，以及大脑周围脑脊液 (CSF) 内最终的炎症反应。该项目将全面了解 T 细胞如何靶向LGI1抗体脑炎中的LGI1肽，并最终导致新的LGI1特异性T细胞靶向治疗的开发。ApproachI将使用将LGI1蛋白分裂成小片段产生的小肽来激活LGI1患者外周血中的T细胞抗体脑炎。这将确定哪些 LGI1 肽是这种情况下 T 细胞反应的基础。然后可以将这些肽加载到抗原呈递分子中，并用于从外周血中分离 LGI1 反应性 T 细胞。然后我将利用创新的单细胞测序技术，这使我能够测量个体中每个基因的表达水平细胞，并对其 T 细胞受体序列进行测序。该方法将用于研究胸腺中的 LGI1 反应性发育 T 细胞，以及 LGI1 抗体脑炎患者和对照受试者的外周血和脑脊液中的 LGI1 反应性发育 T 细胞。同时，我将在胸腺样本上使用一种称为 CODEX 的方法。这种方法使我能够同时检查许多蛋白质的丰度和分布。我将用它来了解 LGI1 肽如何呈递给发育中的 T 细胞，以及自身反应性 T 细胞如何逃脱阴性选择进入外周血。影响该项目将确定 LGI1 反应性 T 细胞如何逃脱胸腺中的阴性选择。我还将展示 LGI1 抗体脑炎患者中哪些亚型的 T 细胞会对 LGI1 肽产生反应，并了解这如何导致脑部炎症。这可能会揭示 LGI1 抗体脑炎的新机制，从而导致针对性的治疗措施，旨在特异性抑制 LGI1 反应性 T 细胞，同时使其他 T 细胞不受影响。这些结果对于理解 T 细胞在其他神经免疫疾病中的作用，以及 T 细胞肽反应性在更广泛的自身免疫性疾病、癌症和传染病中的作用也很重要。