Genetic Elements that Influence Susceptibility to CNS Autoimmunity

影响中枢神经系统自身免疫易感性的遗传因素

• 批准号: 7176038
• 负责人: ANA C ANDERSON
• 金额: $ 17.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-03 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176038
• 关键词: Affect; Alleles; Animal Model; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; CNS autoimmunity; Complement; Congenic Strain; Development; Diabetes Mellitus; Disease; Disease susceptibility; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Genes; Genetic; Genome; Human; Immunization; Inbred NOD Mice; Inbred Strains Mice; Insulin-Dependent Diabetes Mellitus; Knowledge; Microsatellite Repeats; Mouse Strains; Myelin; Personal Satisfaction; Predisposition; Production; RNA Splicing; Resistance; Resources; Screening procedure; Self Tolerance; T-Lymphocyte; Testing; Transgenic Mice; Transgenic Organisms; Twin Studies; Variant; autoreactive T cell; congenic; cytokine; genetic element; tool

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.

描述（由申请人提供）：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，可以通过髓磷脂抗原免疫在实验动物中诱导。 MS 的家族聚集和双胞胎研究以及近交系小鼠对 EAE 易感性的差异表明这些疾病的遗传因素。使用微卫星标记进行全基因组筛选已鉴定出几个影响 EAE 易感性的基因座。有趣的是，针对 EAE 鉴定的基因座与其他自身免疫性疾病（包括 NOD 小鼠的 I 型糖尿病）中鉴定的基因座重叠，因此增加了相同遗传元件或“常见自身免疫基因”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基因的实际共享。有助于 NOD 小鼠易感性的基因座（指定为 Idd）已被明确定义，并且可获得几个同系系，其中来自抗性菌株的 Idd 基因座已渗入 NOD 背景上。 NOD 小鼠对 EAE 敏感，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。转基因 TcR 在适当的遗传和同源背景上的表达提供了精确的工具来识别易感位点可能影响自身反应性 T 细胞的发育和功能的机制。然而，目前尚无可在 NOD 背景下产生 EAE 的 TcR 转基因小鼠品系。为了利用NOD背景上可用的同类菌株来进一步了解影响研究中枢神经系统自身免疫的遗传因素，我们建议：1）首先在NOD背景上生成对MOG 35-55特异的TcR转基因小鼠，以便可以测试抗性和易感性等位基因对致脑炎T细胞发育的影响。 TcR 转基因小鼠还将接受 T 细胞选择、细胞因子产生、自发性和诱导性 EAE 测试。 2) 研究Idd3位点调节自我耐受和EAE发生的机制。 3) 检查liCTLA-4剪接变体是否负责Idd5.1遗传区间与自身免疫性疾病易感性的关联。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。