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.

背景肌免疫性脑炎是指由于免疫反应误导而引起的脑部炎症。这种情况会导致许多症状，包括记忆力丧失，癫痫发作和精神病问题。反对富含亮氨酸胶质瘤的自身抗体灭活1（LGI1）会导致LGI1抗体脑炎，这是最常见的自身免疫性脑脑炎。尽管可以使用类固醇和其他免疫疗法，但LGI1抗体脑炎的患者尽管有最佳治疗，但仍会长期存在情绪，记忆和疲劳的问题。尽管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抗体诱发性疾病中也很重要。 T细胞是免疫细胞，使用T细胞受体来识别称为肽的特定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细胞提供了针对感染和肿瘤的有效防御，但是当它们与自然存在于体内的肽反应时会引起自身免疫性。T细胞在一个称为胸腺的器官中发育，其中通过称为负选择的过程消除了识别自肽的T细胞。 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)该项目将全面地了解LGI1抗体脑炎中的LGI1肽如何靶向LGI1肽，并最终导致发展新的LGI1特异性T细胞细胞靶向治疗。将使用通过将LGI1蛋白蛋白从peripip santib saterip santip santip santip santy perip perip periperpy lg the ploperpy lg the pyperpy lg pyperpy floperpy lg thery plold perpyly lg perpyly lg the perpyly lg perpyly。这将确定在这种情况下T细胞反应的基础的LGI1肽。然后可以将这些肽加载到抗原呈递分子中，并用于将LGI1反应T细胞与外周血分离。I然后将利用创新的单细胞测序技术，这使我能够测量单个细胞中每个基因的表达水平，以及其T细胞的T细胞受体序列。该方法将用于研究胸腺中的LGI1反应性发育中的T细胞，以及来自LGI1抗体脑炎和对照受试者的外周血和CSF中的LGI1反应性T细胞。这种方法使我能够同时检查许多蛋白质的丰度和分布。我将使用它来了解如何将LGI1肽呈现给开发T细胞，从而自我反应性T细胞如何逃脱为外围血液中的负选择。Impactthis项目将确定LGI1反应性T细胞如何在胸腺中逃脱负面选择。我还将显示LGI1抗体脑炎患者中T细胞的亚型对LGI1肽的反应，并了解这如何导致脑部炎症。这很可能会发现LGI1抗体脑炎的基本机制，该机制将导致针对特定抑制LGI1反应T细胞的目标治疗方法，同时使其他T细胞未受影响。这些结果对于理解T细胞在其他神经免疫性疾病中的作用以及T细胞肽反应性在自身免疫性疾病中的作用也将很重要，在癌症和传染病中更广泛地在自身免疫性疾病中。