B CELL HYPERACTIVITY IN AUTOIMMUNITY

表达隐性常染色体突变lpr或gld的小鼠， 出现与大量淋巴增生相关的自身免疫综合征 和自身抗体的过度产生。 由于自身抗体 这些小鼠产生的特异性与患者相似 患有SLE和其他系统性自身免疫性疾病， 被认为是人类疾病的有用模型。 lpr和gld突变 最近被定位到编码细胞表面的基因上 分子APO-1/Fas和Fas-配体。 Fas/Fas配体 相互作用已被证明密切参与细胞凋亡， 与钙非依赖性T细胞介导的细胞毒性相关的途径 与活化相关的外周T细胞耐受机制 诱导细胞死亡。 活化的B细胞也表达Fas抗原， 该实验室和其他涉及嵌合小鼠的研究表明， 然而，在lpr/lpr中，B细胞与正常B细胞本质上不同， Fas/Fas-配体相互作用在常规B细胞中实际作用 答案是未知的。 目前的建议将涉及以下方面的作用： Fas/Fas配体在常规B细胞免疫调节中的作用及意义 试图确定为什么正常的B细胞存活和功能 在[LPR +野生型]嵌合环境中抑制。 这些问题将 通过以下具体目标来解决：（1）调查如何 不同的体外活化和细胞因子信号调节Fas和Fas- T和/或B淋巴细胞亚群中的配体表达，并鉴定 负责体内Fas-配体的细胞和条件 （2）确定组成性Fas的功能后果 表达对lpr、gld和+/+宿主中B细胞存活和功能的影响 通过生产和分析遗传B基因的转基因小鼠， 谱系限制性Fas转基因;（3）评估 来自不能有效表达Fas和 Fas-配体，即双突变lpr/lpr gld/gld冰;和（4）比较 正常、lpr和lpr β 2-微球蛋白KO的中枢反应 小鼠在量级、动力学、抗体多样化和 亲和力成熟 更好地了解其病因 从这些研究中获得的自身免疫应直接适用于 人类疾病的治疗。

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.