Genetic Elements that Influence Susceptibility to CNS Autoimmunity

实验性自身免疫性脑脊髓炎（EAE）是一种人类MS的动物模型，可用于 在实验动物中通过用髓鞘抗原免疫诱导。家族聚集性和双胞胎 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。利用微卫星标记进行全基因组筛选， 鉴定影响EAE易感性几个基因座。有趣的是，EAE的基因座 与在其他自身免疫性疾病中发现的基因座重叠，包括在糖尿病中的I型糖尿病。 NOD小鼠，从而提高了相同的遗传元件或“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。不管这是巧合还是因为 基因的实际共享目前尚不清楚。基因座（命名为Idd），有助于易感性， NOD小鼠已经被很好地定义，并且几个同源系中，来自抗性小鼠的Idd基因座 菌株已渗入NOD背景是可用的。NOD小鼠易患EAE 从而使得可以利用该资源来进一步分析蜂窝， 导致EAE易感性的遗传因素。转基因TcRs在合适的细胞上表达， 遗传和同源背景提供了一个精确的工具，以确定易感性的机制， 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， 小鼠品系，可以发展EAE的NOD背景。 为了利用NOD背景下的同类菌株，进一步了解 为了研究影响CNS自身免疫的遗传因素，我们建议：JJ首先产生TcR 在NOD背景下对MOG 35-55特异的转基因小鼠， 可以测试易感性等位基因对致脑炎性T细胞发育的影响。TcR转基因小鼠 还将测试T细胞选择、细胞因子产生、自发性和诱导性EAE。2|检查 Idd 3基因座调节自身耐受性和EAE发展的机制。审查 iCTLA-4剪接变体是否负责Idd5.1遗传区间与 自身免疫性疾病的易感性。 这些研究将补充正在进行的关于Idd基因座对I型糖尿病发展的影响的研究。 NOD小鼠的糖尿病，并将加速对影响CNS发育的基因的分析 自身免疫

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.