Genetics of systemic autoimmunity in mouse models of lupus.
Genetics of systemic autoimmunity in mouse models of lupus.
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DOI：
10.3109/08830180009055504
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发表时间：
2000-01-01
影响因子：
5
通讯作者：
Theofilopoulos, A N
中科院分区：
文献类型：
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作者：
Kono, D H;Theofilopoulos, A N
系统性红斑狼疮（SLE）是一种复杂的多基因性状，涉及遗传、环境和随机因素。尽管这些病因过程的定义一直难以捉摸，但在阐明易感性的遗传基础方面已经取得了坚实的进展。在此，我们总结了我们的全基因组作图工作，该工作已定义了狼疮易发性 NZB、NZW、MRL-Fas(lpr) 和 BXSB 菌株的组成表型基因座。有了这个框架，具体的遗传改变和机制的鉴定现在正在通过区间同源系的生成、候选基因的精确定位和筛选进行。除了这种方法之外，转基因和基因敲除研究已经开始鉴定可以在非自身免疫和狼疮倾向背景小鼠中诱导或改变自身免疫的基因，包括我们和其他人对狼疮中 Th1 和 Th2 细胞因子基因的研究。显然，多种基因和机制可以独立或联合促进小鼠的系统性自身免疫。这种复杂性也在人类狼疮中观察到，强调了使用实验性和不太复杂的小鼠模型来定义这些过程的重要性，这种策略已经产生了新的见解。利用当前技术和哺乳动物基因组的预期定义，识别狼疮易感基因并阐明疾病发病机制的关键过程似乎已成为可能。
Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait, involving genetic, environmental and stochastic factors. Although definition of these etiologic processes has been elusive, solid progress has been made toward elucidating the genetic basis for susceptibility. Herein, we summarize our genome wide mapping effort that has defined loci for component phenotypes for lupus-prone NZB, NZW, MRL-Fas(lpr) and BXSB strains. With this framework in place, identification of the specific genetic alterations and mechanisms is now proceeding through the generation of interval congenic lines, precise mapping and screening of candidate genes. In addition to this approach, transgenic and gene knockout studies have begun to identify genes that can induce or modify autoimmunity in nonautoimmune and lupus-prone background mice, including studies by us and others on Th1 and Th2 cytokine genes in lupus. It is apparent that a diversity of genes and mechanisms can independently or in combination promote systemic autoimmunity in mice. This complexity, which is also observed in human lupus, emphasizes the importance of using experimental and less complex mouse models to define these processes, a tactic that has already yielded new insights. With current technologies and the anticipated definition of mammalian genomes, identification of genes predisposing to lupus and elucidation of processes critical for disease pathogenesis appear within grasp.