The genes of systemic autoimmunity.
The genes of systemic autoimmunity.
复制标题
DOI：
10.1046/j.1525-1381.1999.99244.x
复制
发表时间：
1999-05
期刊：
影响因子：
--
通讯作者：
A. Theofilopoulos;D. Kono
中科院分区：
文献类型：
--
作者：
A. Theofilopoulos;D. Kono
自身免疫性疾病包括多种疾病，分为全身性疾病和器官特异性疾病。狼疮是一种典型的系统性自身免疫性疾病，其特征是女性占主导地位、多器官病理学和主要针对核抗原的自身抗体。该疾病具有异质性，受累器官、血清学和临床病程各不相同。对狼疮的易感性是作为多基因性状遗传的，并且环境和随机方差也有额外的贡献。最近，几个实验室共同努力，在易感小鼠和人类中确定了这种疾病的遗传基础。 lpr 和 gld 狼疮小鼠中 Fas/FasL 缺陷的鉴定是促凋亡基因自发突变与系统性自身免疫相关的第一个例子。这项研究有助于阐明这些基因在耐受性和免疫调节中的作用，并将这些结果外推到其他自身免疫性疾病以及癌症和移植。除了这些发现之外，还添加了转基因和基因敲除小鼠研究的结果，这些研究有助于确定特定基因在正常背景和狼疮同源小鼠中的系统性自身免疫诱导或修饰作用。此外，全基因组搜索的结果已开始在各种小鼠品系和人类中识别出自发性狼疮样疾病的易感位点（以及最终的基因）。正在出现的情况是，多种遗传贡献可以独立导致小鼠的系统性自身免疫，这强化了人类狼疮可能类似地由不同基因型组成的观点。这种复杂性强调了定义诱发等位基因和作用机制的重要性，鉴于哺乳动物基因组定义的当前技术和未来进展，这项工作当然是可行的。
Autoimmune diseases include a wide spectrum of disorders, which have been divided into systemic and organ-specific disorders. Lupus, the prototypic systemic autoimmune disease, is characterized by female predominance, multiorgan pathology, and autoantibodies, primarily directed against nuclear antigens. The disease is heterogeneous, with variable organ involvement, serology, and clinical course. Susceptibility to lupus is inherited as a polygenic trait with added contributions from environmental and stochastic variance. Concerted efforts have recently been made by several laboratories to define the genetic basis of this disease in predisposed mice and humans. The identification of the Fas/FasL defects in lpr and gld lupus mice was the first example of spontaneous mutations of apoptosis-promoting genes being associated with systemic autoimmunity. This research was instrumental in clarifying the roles of these genes in tolerance and immunoregulation, and in extrapolating these results to other autoimmune diseases, as well as cancer and transplantation. To these findings have been added those from transgenic and gene knockout mouse studies that have helped to define the systemic autoimmunity-inducing or -modifying effects of specific genes in normal background and lupus-congenic mice. In addition, the findings from genome-wide searches have begun to identify predisposing loci (and ultimately genes) for the spontaneous lupus-like diseases in various mouse strains and in humans. The emerging picture is that multiple genetic contributions can independently lead to systemic autoimmunity in mice, which reinforces the view that human lupus may be similarly composed of diverse genotypes. This complexity underscores the importance of defining the predisposing alleles and mechanisms of action, an undertaking that is certainly feasible given current technologies and future advances in the definition of mammalian genomes.