B CELL HYPERACTIVITY IN AUTOIMMUNITY

表达隐性常染色体突变的小鼠，LPR或GLD， 发展为与大量淋巴组织增生相关的自身免疫综合征 以及过多的自身抗体产生。由于自身抗体的范围 这些小鼠产生的特异性与患者相似 他们患有系统性红斑狼疮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 APO-1/Fas分子和Fas-Ligand分子。Fas/Fas-配体 相互作用已被证明与细胞凋亡密切相关。 钙非依赖性T细胞介导的细胞毒作用途径 以及与激活相关的外周T细胞耐受机制 诱导细胞死亡。活化的B细胞也表达Fas抗原和 来自这个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细胞固有地不同 Fas/Fas-配体相互作用在常规B细胞中的实际作用 人们对此的反应尚不清楚。目前的提案将涉及到 Fas/Fas配体在调节B细胞免疫功能中的作用 试图确定为什么正常的B细胞存活和功能 在[LPR+Wildtype]嵌合环境中被抑制。这些问题将 通过以下具体目标加以解决：(1)调查如何 不同的体外激活和细胞因子信号调节Fas和Fas- T和/或B淋巴细胞亚群中配体的表达及鉴定 体内Fas配体产生的细胞和条件 表达；(2)确定组成性Fas的功能后果 LPR、GLD和+/+宿主中B细胞存活和功能的表达 通过制造和分析遗传B基因的转基因小鼠来保护环境 家系限制性Fas转基因；(3)评价Fas基因的功能特性 小鼠淋巴细胞不能同时有效表达Fas和Fas Fas配体，即双突变体LPR/LPR GLD/GLD；以及(4)比较 正常、LPR和LPRβ2-微球蛋白KO的生发中心反应 小鼠在数量、动力学、抗体多样性和 亲和力成熟。对本病病因的更好理解 从这些研究中获得的自身免疫应该直接适用于 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.