Genetic Elements that Influence Susceptibility to CNS Autoimmunity

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种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。多发性硬化症的家族聚集和双胞胎研究以及小鼠近交菌株对EAE的易感性差异表明，这些疾病的遗传成分。利用微卫星标记进行全基因组筛选，鉴定出了几个影响EAE易感性的位点。有趣的是，在NOD小鼠中发现的EAE基因座与在其他自身免疫性疾病（包括I型糖尿病）中发现的基因座重叠，从而提高了相同遗传元件或“共同自身免疫性基因”可能导致多种自身免疫性疾病易感性的可能性。目前尚不清楚这是巧合还是由于实际的基因共享。在NOD小鼠中，导致易感性的基因座（指定的Idd）已经被很好地定义，并且在一些同源系中，来自耐药菌株的Idd基因座已经渗入到NOD背景中。NOD小鼠对EAE易感，因此可以利用这一资源进一步分析导致EAE易感性的细胞和遗传因素。在适当的遗传和遗传背景下，转基因tcr的表达为鉴定易感位点可能影响自身反应性T细胞发育和功能的机制提供了精确的工具。然而，目前还没有TcR转基因小鼠品系能够在NOD背景下发生EAE。为了利用NOD背景下现有的同源菌株，进一步了解影响中枢神经系统自身免疫的遗传因素，我们提出：1)首先在NOD背景下制备特异性MOG 35-55的TcR转基因小鼠，以便检测耐药和易感等位基因对脑源性T细胞发育的影响。TcR转基因小鼠还将进行T细胞选择、细胞因子产生、自发和诱导EAE的测试。2)研究Idd3基因座调控自身耐受性和EAE发生的机制。3)研究liCTLA-4剪接变异体是否与Idd5.1遗传间隔与自身免疫性疾病易感性相关。这些研究将补充正在进行的Idd基因座对NOD小鼠I型糖尿病发展影响的研究，并将加速对影响中枢神经系统自身免疫发展的基因的分析。

DESCRIPTION (provided by applicant): 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: 1) 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.