利用TCRβ CDR3组库分析筛选SLE患者T细胞治疗精准靶标

Currently, the main problem of SLE targeted therapy is the lack of specificity which is unable to distinguish between autoreactive lymphocyte and normal lymphocyte. How to improve precision of the target treatment becomes an important problem in treatment of SLE. In recent years, Immune Repertoire had been widely used in the development of vaccine and medicine and in the discovery of biomarkers. In our previous studies, we analyzed the changes of TCRβ CDR3 repertoire and BCR-H CDR3 repertoire from two cases of SLE patients after high dose of glucocorticoid treatment. These results suggested that only few T cells might involve in the pathogenesis of SLE, while B cell was not suitable as an accurate target due to the presence of high frequency mutation. Therefore, this project proposed a key scientific problem: how to determine the markers and characteristic CDR3 of these few T cells that involved in the pathogenesis of SLE? In order to solve the problem, this project had designed three research contents, including the analysis of homology and heterogeneity of TCRβ repertoire of Th subsets between peripheral blood and renal biopsy, screening public CDR3 from Th subsets between peripheral blood and renal biopsy and analysis of correlation between TCRβ repertoire of peripheral Th subsets and clinically relevant index scores and serological detection. The implement of this project will provide important basis data and new idea for precise targeted therapy of T cell in SLE.

当前，SLE的靶向治疗药物面临的主要问题是特异性不强，即无法区分自身反应淋巴细胞和正常淋巴细胞，如何改善靶向治疗精准度成为SLE治疗的重要问题。近年来，免疫组库被广泛应用于疫苗和医药研发、生物标志物发现。本项目在前期研究中分析了两例SLE患者TCRβ CDR3库和BCR-H CDR3库在大剂量糖皮质激素治疗后的变化，提示仅少数T细胞群体参与了SLE的发病，而B细胞由于存在高频突变不适于作为精准靶标。因此，本项目提出一个关键科学问题：如何确定参与SLE发病的少数T细胞标志物和特征性CDR3？本项目拟通过三个方面内容以解决该问题，包括分析外周血和肾活检组织Th亚群TCRβ库的同源性与异质性、筛选外周血Th亚群与肾活检组织Th亚群公共CDR3和分析外周血各Th亚群TCRβ库与其临床相关评分指数及血清学检测的相关性。本项目的开展将为SLE的T细胞精准靶向治疗策略提供重要数据和新思路。

当前，SLE的靶向治疗药物面临的主要问题是特异性不强，即无法区分自身反应淋巴细胞和正常淋巴细胞，如何改善靶向治疗精准度成为SLE治疗的重要问题。近年来，免疫组库被广泛应用于疫苗和医药研发、生物标志物发现。本项目在前期研究中分析了两例SLE患者TCRβ CDR3库和BCR-H CDR3库在大剂量糖皮质激素治疗后的变化，提示仅少数T细胞群体参与了SLE的发病，而B细胞由于存在高频突变不适于作为精准靶标, 因此，本项目拟利用TCRβ CDR3库测序分析去筛选SLE治疗的精准靶标。经实验方案调整后，我们通过Illumina NovaSeq测序和分析活动期与缓解期SLE患者的TCRαβ CDR3库，发现SLE患者TCRα和TCRβ CDR3库的多样性均低于对照组，且SLE组CDR3的克隆分布呈现高频克隆的频率明显多于对照组，这些差异主要源自基因重排或和核苷酸缺失的差异。通过对共有CDR3分析, 我们筛到了一些TCRα、TCRβ CDR3克隆，可推荐用于潜在的SLE的精准治疗靶标。此外，我们通过转录组分析发现，SLE发病相关活化的T细胞的亚群主要为Th17、Th1、Th2，因此，我们也推荐通过刺激Treg增殖而抑制这些炎症反应亚群活化治疗方案。

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