GENETIC ANALYSIS OF T CELLS IN LUPUS

狼疮 T 细胞的遗传分析

• 批准号: 6171561
• 负责人: Joseph Edgar Craft
• 金额: $ 32.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171561
• 关键词: B lymphocyte; CD40 molecule; T cell receptor; autoantibody; cell population study; genetically modified animals; glomerulonephritis; helper T lymphocyte; human subject; hybridomas; immune tolerance /unresponsiveness; immunogenetics; laboratory mouse; leukopoiesis; monoclonal antibody; systemic lupus erythematosus; tissue /cell culture

MRL-lpr/lpr and MRL-+/+ mice develop a disease that resembles human SLE, including the production of autoantibodies to small nuclear ribonucleoprotein particles (snRNPs) and to chromatin (DNA and histones), and development of immune-complex glomerulonephritis. Current data indicates that disease-specific and pathogenic autoantibodies in murine and human lupus undergo somatic mutation and affinity maturation. These findings have given rise to the paradigm that autoreactive B cells in lupus require cognate, presumably autoantigen-specific, and contact- dependent, alphabetaT cell help. To further investigate the role of conventional alphabeta T cell help in autoantibody production, alphabeta T cell-deficient MRL-lpr/lpr mice and MRL-lpr/lpr mice that lack CD40 ligand (CD40L), an essential T cell signal for initiating immunoglobulin synthesis and class switching by B cells, have been generated. Notably, these animals developed hypergammaglobulinemia and IgG anti-snRNP antibodies. Certain ones (alphabeta T cell-deficient MRL-lpr/lpr mice) also developed renal immune deposits and delayed renal insufficiency; however, both the alphabeta T cell- and CD40L-deficient MRL mice lacked high titer, high-affinity anti-DNA antibodies and overt, early nephritis typical of wild type MRL disease. Based upon these findings, hypotheses are offered that autoantibody production in murine lupus does not absolutely depend upon conventional, alphabeta T cell help, and that the MRL phenotype is a consequence of both alphabeta cell-dependent and alphabeta T cell-independent mechanisms. To address these hypotheses, genetic approaches and reconstitution experiments will be used to determine the respective requirements for conventional alphabeta and non- conventional B cell help for autoantibody production and renal injury in MRL lupus. The features of alphabeta T cells that contribute to the genesis of the wild type MRL phenotype will also be assessed. Finally, the autoantibodies that arise in mice lacking conventional T cell help will be characterized, and their in vivo pathogenicity assessed.

MRL-LPR/LPR和MRL-+/+小鼠发展出一种类似于人类SLE的疾病， 包括产生针对小核的自身抗体 核糖核蛋白颗粒(SnRNPs)和染色质(DNA和组蛋白)， 发展为免疫复合型肾小球肾炎。当前数据 提示小鼠体内的疾病特异性和致病性自身抗体 人类狼疮经历了体细胞突变和亲和力成熟。这些 这些发现引发了一种范式，即自身反应性B细胞 狼疮需要同源的，可能是自身抗原特异的，以及接触- 依赖，字母T细胞帮助。为了进一步调查 传统的Alphabeta T细胞有助于自身抗体的产生 T细胞缺陷的MRL-LPR/LPR小鼠和缺乏CD40的MRL-LPR/LPR小鼠 配体(CD40L)--启动免疫球蛋白的基本T细胞信号 已经产生了B细胞的合成和类别转换。值得注意的是， 这些动物出现了高丙种球蛋白血症和抗SNRNP的抗体。 抗体。某些(Alphabeta T细胞缺陷的MRL-LPR/LPR小鼠) 还出现肾脏免疫沉积和延迟性肾功能不全； 然而，Alphabeta T细胞和CD40L缺陷的MRL小鼠都缺乏 高滴度、高亲和力抗DNA抗体与早期显性肾炎 典型的野生型MRL病。基于这些发现，假设 在小鼠狼疮中产生自身抗体并不是 完全依赖于常规的Alphabeta T细胞帮助，而 MRL表型是α-β细胞依赖和 Alphabeta T细胞非依赖机制。为了解决这些假设， 遗传方法和重建实验将被用于 确定常规Alphabeta和非Alphabeta的各自要求 常规B细胞在自身抗体产生和肾损伤中的作用 核磁共振成像狼疮。阿尔法贝塔T细胞的特性对 野生型MRL表型的起源也将被评估。最后， 在缺乏常规T细胞帮助的小鼠中产生的自身抗体 将被表征，并评估它们在体内的致病性。