B CELL HYPERACTIVITY IN AUTOIMMUNITY

自身免疫中的 B 细胞过度活跃

• 批准号: 2079040
• 负责人: Ann Marshak-Rothstein
• 金额: $ 26.69万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-22 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2079040
• 关键词: B lymphocyte; SCID mouse; apoptosis; autoantibody; autoimmune disorder; cell population study; disease /disorder model; gene expression; gene mutation; genetic strain; genetically modified animals; immunogenetics; immunoregulation; laboratory mouse; leukocyte activation /transformation; leukopoiesis; systemic lupus erythematosus

Mice expressing either of the recessive autosomal mutations, lpr or gld, develop autoimmune syndromes associated with massive lymphoid hyperplasia and excessive autoantibody production. Since the range of autoantibody specificities produced by these mice is similar to that of patients afflicted with SLE and other systemic autoimmune diseases, they have been considered a useful model for human disease. The lpr and gld mutations have recently been mapped to the genes that encode the cell surface molecules APO-1/Fas and Fas-ligand, respectively. Fas/Fas-ligand interactions have been shown to be intimately involved in the apoptotic pathways associated with calcium-independent T cell-mediated cytotoxicity and peripheral T cell tolerance mechanisms associated with activation induced cell death. Activated B cells also express the Fas antigen and studies from this lab and others involving chimeric mice have shown that in lpr/lpr B cells are inherently different from normal B cells, however the actual role of Fas/Fas-ligand interactions in conventional B cells responses is unexplored. The current proposal will address the role of Fas/Fas-ligand in the regulation of conventional B cell immunity and attempt to determine why normal B cell survival and function are suppressed in an [lpr + wildtype] chimeric environment. These issues will be addressed through the following specific aims: (1) Investigate how different in vitro activation and cytokine signals regulate Fas and Fas- ligand expression in T and/or B lymphocyte subpopulations and identify the cells and conditions that are responsible for in vivo Fas-ligand expression; (2) Determine the functional consequences of constitutive Fas expression on B cell survival and function in lpr, gld and +/+ host environments by producing and analyzing transgenic mice that inherit a B lineage restricted Fas transgene; (3) Assess the functional properties of lymphocytes from mice incapable of effectively expressing both Fas and Fas-ligand, i.e. double mutant lpr/lpr gld/gld ice; and (4) Compare the germinal center response of normal, lpr, and lpr beta2-microglobulin KO mice with regard to magnitude, kinetics, antibody diversification, and affinity maturation. The better understanding of the etiology of autoimmunity gained from these studies should be directly applicable to the treatment of human disease.

表达一个隐性常染色体突变的小鼠LPR或GLD， 发展与大量淋巴增生相关的自身免疫性综合征 和过量的自身抗体产生。 由于自身抗体范围 这些小鼠产生的特异性与患者相似 遭受SLE和其他系统性自身免疫性疾病的困扰，它们一直 被认为是人类疾病的有用模型。 LPR和GLD突变 最近已映射到编码细胞表面的基因 分子apo-1/fas和fas配体分别。 FAS/FAS-配体 相互作用已被证明与凋亡密切相关 与钙独立的T细胞介导的细胞毒性相关的途径 与激活相关的外围T细胞耐受性机制 诱导细胞死亡。 活化的B细胞还表达FAS抗原和 该实验室和其他涉及嵌合小鼠的研究表明 在LPR/LPR B细胞中，与正常B细胞​​固有不同，但是 FAS/FAS - 配体相互作用在常规B细胞中的实际作用 响应未开发。 当前的提议将解决 常规B细胞免疫和 尝试确定为什么正常B细胞​​的存活和功能是 在[LPR + WildType]嵌合环境中抑制。 这些问题会 通过以下特定目的解决：（1）调查如何 不同的体外激活和细胞因子信号调节FA和FAS- T和/或B淋巴细胞亚群中的配体表达，并确定 负责体内FAS配体的细胞和条件 表达; （2）确定本构FAS的功能后果 LPR，GLD和 +/ +主机中B细胞存活和功能的表达 通过产生和分析继承A B的转基因小鼠的环境 谱系限制的FAS转基因； （3）评估功能特性 来自小鼠的淋巴细胞无法有效地表达FAS和 FAS-Ligand，即双突变体LPR/LPR GLD/GLD冰； （4）比较 正常，LPR和LPR beta2-微球蛋白KO的生发中心反应 小鼠关于大小，动力学，抗体多样化和 亲和力成熟。 对病因的更好理解 从这些研究中获得的自身免疫性应直接适用于 人类疾病的治疗。