Genetic Elements that Influence Susceptibility to CNS Autoimmunity

实验性自身免疫性脑脊髓炎(EAE)是人类多发性硬化症的动物模型，可以 通过髓鞘抗原免疫在实验动物中诱导的。既有家族聚集性又有双胞胎 MS研究和近交系小鼠对EAE易感性的差异表明 这些疾病的组成部分。使用微卫星标记的全基因组筛查导致了 确定几个影响EAE易感性的基因座。有趣的是，确定的EAE基因座 与在其他自身免疫性疾病中已发现的基因座重叠，包括在 NOD小鼠，从而增加了相同的遗传因素或“共同的自身免疫基因”的可能性 可能导致对多种自身免疫性疾病的易感性。无论这是巧合还是由于 目前尚不清楚基因的实际共享情况。易感基因座(指定为Idd) NOD小鼠已经被很好地定义，并在几个同源系中从抗性 菌株已被导入的点头背景可用。NOD小鼠对EAE易感 从而有可能利用这一资源来进一步分析细胞和 导致EAE易感性的遗传因素。转基因TCRs在宿主细胞中的表达 遗传和同源背景为确定易感性的机制提供了一种精确的工具 基因座可能影响自身反应性T细胞的发育和功能。然而，没有TCR转基因 可获得的小鼠品系可以在点头背景上发展为EAE。 利用NOD背景上可用的同源菌株来加深我们对 影响中枢神经系统自身免疫的遗传因素研究，我们建议：JJ首先产生TCR 转基因小鼠特异性针对MOG35-55的结节背景使其产生抗性和 可以检测脑源性T细胞发育的易感等位基因。TCR转基因小鼠 还将测试T细胞选择、细胞因子产生、自发性和诱发性EAE。2|查看 Idd3基因座调节自身耐受性和EAE.3发育的机制。考查 LiCTLA-4剪接变异体是否导致Idd5.1遗传区间与 易患自身免疫性疾病。 这些研究将补充正在进行的IDD基因座对I型糖尿病发展的影响的研究 在NOD小鼠中发现糖尿病，并将加速分析影响中枢神经系统发育的基因 自身免疫力。

Experimental autoimmune encephalomyelitis (EAE) is an animal model for human MS that can be induced in experimental animals by immunization with myelin antigens. Both familial aggregation and twin studies in MS and the difference in the susceptibility to EAE in inbred strains of mice suggest a genetic component to these diseases. Genome wide screening using microsatellite markers has led to the identification of several loci that influence susceptibility to EAE. Interestingly, the loci identified for EAE overlap with the loci that have been identified in other autoimmune diseases, including type I diabetes in the NOD mouse, thus raising the possibility that the same genetic elements or "common autoimmune genes" may contribute to susceptibility to multiple autoimmune diseases. Whether this is coincidental or due to actual sharing of genes is not currently known. The loci (designated Idd) that contribute to susceptibility in the NOD mouse have been well defined and several congenic lines in which the Idd loci from the resistant strain have been introgressed on the NOD background are available. NOD mice are susceptible to EAE thereby making it possible to take advantage of this resource to further the analysis of the cellular and genetic factors that contribute to susceptibility to EAE. The expression of transgenic TcRs on appropriate genetic and congenic backgrounds provides a precise tool to identify the mechanisms by which susceptibility loci may affect the development and function of autoreactive T cells. However, there is no TcR transgenic mouse strain available that can develop EAE on the NOD background. To take advantage of the congenic strains available on the NOD background to further our knowledge of the genetic elements that influence study CNS autoimmunity, we propose to: JJ First generate a TcR transgenic mouse specific for MOG 35-55 on the NOD background so that the effect of resistance and susceptibility alleles on the development of encephalitogenic T cells can be tested. The TcR transgenic mice will also be tested for T cell selection, cytokine production, spontaneous and induced EAE. 2| Examine the mechanism by which the Idd3 locus regulates self-tolerance and the development of EAE.3). Examine whether the liCTLA-4 splice variant is responsible for the association of the Idd5.1 genetic interval with susceptibility to autoimmune disease. These studies will complement ongoing studies of the effects of Idd loci on the development of Type I diabetes in the NOD mouse and will accelerate the analysis of the genes affecting the development of CNS autoimmunity.