Genetic Analysis of T Cells in Lupus

狼疮 T 细胞的遗传分析

• 批准号: 6646996
• 负责人: Joseph Edgar Craft
• 金额: $ 40.88万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646996
• 关键词: B lymphocyte; MHC class II antigen; antibody formation; autoantibody; cell cell interaction; cell population study; cellular pathology; disease /disorder model; genetically modified animals; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by IgG autoantibodies to certain intracellular components, including chromatin and ribonucleoproteins. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Certain of these specificities are pathogenic, including those against chromatin that induce immune-complex glomerulonephritis. Autoantibodies in lupus arise as a consequence of autoantigen-specific alpha/beta CD4+ T cell help, including T cells specific for peptides of chromatin-associated proteins. Such autoreactive T cells bypass normal tolerance mechanisms in the periphery; however, the mechanism of activation of T cells responsive to self peptides in lupus is unknown, as are the tissue source(s) of such peptides and the events leading to autoreactive CD4+ T cell-B cell collaboration with resultant pathogenic autoantibody production. In this proposal, an in vivo approach will be used to dissect the mechanisms that lead to peripheral T cell tolerance abrogation and T cell help for autoantibody production in lupus. It is hypothesized that these events arise in two stages: first, that lupus T cells have intrinsic (genetic) defects that render them susceptible to activation after contact with the ubiquitous self peptide-class II MI-IC complexes that are sufficient for CD4+ T cell survival in normal animals; second, that such activation, initiating tolerance loss with polyclonal expansion of autoreactive T cells, leads to oligoclonal T-B cell collaboration in the setting of specific autoantigen presentation by autoreactive B cells. The hypothesis will be addressed in two aims. First, it will be determined if normally displayed (ubiquitous) MHC-self peptide complexes can activate autoreactive T cells from Fas-intact mice MRL/+Fas-lpr mice, in comparison to non-autoimmune control T cells. Second, it will be determined if T cells from MRL/+Fas-lpr mice can provide B cell help in the setting of autoantigen presentation by autoreactive B cells, an event that leads to antigen-specific expansion of cells from both lineages. These objectives fit well within the overall context of this IRPO proposal centered around developing a better understanding of T cell-B cell interactions during the development and maintenance of systemic autoimmunity.

描述(申请人提供)：系统性红斑狼疮(SLE) 以针对某些细胞内成分的免疫球蛋白自身抗体为特征， 包括染色质和核糖核蛋白。几个近交系小鼠也 发展为自发性狼疮，具有相同的自身抗体谱。确定的 这些特异性是致病的，包括那些针对染色质的特异性 诱导免疫复合型肾小球肾炎。狼疮自身抗体的产生是一种 自身抗原特异性的α/βCD4+T细胞帮助的结果，包括T 染色质相关蛋白多肽的特异性细胞。这种自动反应 T细胞在外周绕过正常的耐受机制；然而， 狼疮自身多肽诱导T细胞活化的机制 未知，以及这些肽的组织来源(S)和导致 自身反应性CD4+T细胞-B细胞协同致病 自身抗体的产生。在这项提案中，将使用体内方法来 剖析导致外周T细胞耐受性降低和 T细胞有助于狼疮自身抗体的产生。据推测，这些 事件发生在两个阶段：第一，狼疮T细胞具有内在的(遗传) 缺陷，使它们在接触到 无处不在的自体多肽II类MI-IC复合体，足以产生CD4+T细胞 细胞在正常动物中的存活；第二，这种激活、启动 自身反应性T细胞多克隆扩增导致耐受性丧失 寡克隆T-B细胞在特异性自身抗原设定中的协同作用 由自身反应性B细胞呈递。这一假说将分两部分阐述。 目标。首先，将确定是否正常显示(无处不在的)MHC-SELF 多肽复合体能激活Fas基因缺失小鼠的自身反应性T细胞 MRL/+Fas-LPR小鼠与非自身免疫对照T细胞比较。第二，它 将确定来自MRL/+Fas-LPR小鼠的T细胞是否能提供B细胞帮助 自身反应性B细胞自身抗原提呈的设定，这一事件 导致两个谱系的细胞抗原特异性扩增。这些 目标完全符合以IRPO为中心的提案的总体背景 围绕着更好地理解T细胞和B细胞之间的相互作用 全身性自身免疫的发展和维持。