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Defining the specific features of human thymic B cell subsets, their relationship to primary mediastinal B cell lymphoma and nodular sclerosis Hodgkin lymphoma, and pathogenetic mechanisms in these lymphomas

定义人胸腺 B 细胞亚群的具体特征、它们与原发性纵隔 B 细胞淋巴瘤和结节性硬化性霍奇金淋巴瘤的关系以及这些淋巴瘤的发病机制

基本信息

批准号：
284404559
负责人：
Professor Dr. Martin-Leo Hansmann
金额：
--
依托单位：
Institut für Zellbiologie (Tumorforschung)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/284404559?language=en
关键词：
Defining specific features human thymic

项目摘要

The thymus contains a small population of mature B cells. There is indication from studies in the mouse that these cells have an important role in T cell selection. However, only very little is known about their specific features and functions, and their relationship to conventional peripheral blood B cells in the human. Moreover, thymic B cells are considered as the cell of origin of primary mediastinal B cell lymphoma (PMBCL), and are also discussed as the origin of nodular sclerosis Hodgkin lymphoma (NS-HL) in young adults. But again, molecular studies to clarify the relationship between thymic B cells and the two types of lymphomas are missing. We hypothesize that human thymic B cells represent distinct B cell subsets with unique features and that they represent the cellular origin of PMBCL and NS-HL of young adults. In preparatory work, we identified four subsets of thymic B cells by flow cytometry (cells with the phenotype of naive B cells, IgM memory B cells, class-switched B cells and rare CD30+ B cells). We aim to determine the differentiation stage, clonal composition and intersubset relationship of these thymic B cell subsets by detailed analysis of their B cell receptor repertoire by amplicon next generation sequencing. We plan to comprehensively characterize their specific gene expression pattern in comparison to conventional naive and memory B cells through a transcriptome analysis by RNA sequencing. With this, we aim to obtain insight into the specific immunological features of thymic B cells. By comparison of the gene expression pattern of thymic B cells and isolated tumor cells of PMBCL and NS-HL we will determine the relationship between the normal and malignant cells as a means to clarify whether thymic B cells are the origin of the two types of lymphomas and identify deregulated genes in the lymphoma cells. We will also mine the RNA sequencing data of the lymphomas for mutations and fusion transcripts to identify novel genetic lesions. For selected deregulated or mutated genes we will perform functional studies on lymphoma cell lines to clarify the pathogenetic role of these events. Overall, we aim to perform the first comprehensive characterization of the still enigmatic human thymic B cells, clarify whether PMBCL and NS-HL in young adults are derived from thymic B cells, determine deregulated gene expression in these lymphomas, and reveal novel pathogenetic mechanisms in PMBCL and NS-HL.

胸腺含有少量成熟的B细胞。小鼠研究表明，这些细胞在T细胞选择中发挥重要作用。然而，关于它们的具体特征和功能，以及它们与人类常规外周血B细胞的关系，知之甚少。此外，胸腺B细胞被认为是原发性纵隔B细胞淋巴瘤（PMBCL）的起源细胞，也被认为是年轻人结节硬化型霍奇金淋巴瘤（NS-HL）的起源细胞。但是，同样的，没有分子研究来阐明胸腺B细胞和这两种类型的淋巴瘤之间的关系。我们假设人类胸腺B细胞代表了具有独特特征的不同B细胞亚群，并且它们代表了年轻成人PMBCL和NS-HL的细胞起源。在准备工作中，我们通过流式细胞术鉴定了胸腺B细胞的四个亚群（具有幼稚B细胞表型的细胞、IgM记忆B细胞、类别转换的B细胞和罕见的CD 30 + B细胞）。我们的目的是确定这些胸腺B细胞亚群的分化阶段，克隆组成和亚群间的关系，通过扩增子下一代测序的B细胞受体库的详细分析。我们计划通过RNA测序的转录组分析，与传统的幼稚和记忆B细胞相比，全面表征其特异性基因表达模式。有了这个，我们的目标是获得深入了解胸腺B细胞的特异性免疫学特征。通过比较胸腺B细胞和PMBCL和NS-HL的分离肿瘤细胞的基因表达模式，我们将确定正常细胞和恶性细胞之间的关系，作为阐明胸腺B细胞是否是这两种类型的淋巴瘤的起源和识别淋巴瘤细胞中的失调基因的手段。我们还将挖掘淋巴瘤的RNA测序数据以寻找突变和融合转录本，以识别新型遗传病变。对于选定的失调或突变的基因，我们将进行淋巴瘤细胞系的功能研究，以澄清这些事件的发病作用。总之，我们的目标是进行第一次全面的表征仍然是谜一样的人胸腺B细胞，澄清是否PMBCL和NS-HL在年轻的成年人来自胸腺B细胞，确定这些淋巴瘤的基因表达失调，并揭示新的发病机制PMBCL和NS-HL。