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: 7371005
• 负责人: ANA C ANDERSON
• 金额: $ 17.79万
• 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/7371005
• 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

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.

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，可用于 通过用髓磷脂抗原免疫在实验动物中诱导。家族聚集和双胞胎 对 MS 的研究以及近交系小鼠对 EAE 易感性的差异表明，遗传因素 这些疾病的组成部分。使用微卫星标记进行全基因组筛选已导致 鉴定影响 EAE 易感性的几个位点。有趣的是，确定的 EAE 基因座 与其他自身免疫性疾病中已发现的基因座重叠，包括 I 型糖尿病 NOD小鼠，因此增加了相同遗传元件或“共同自身免疫基因”的可能性 可能导致对多种自身免疫性疾病的易感性。这究竟是巧合还是由于 目前尚不清楚基因的实际共享。有助于易感性的位点（指定为 Idd） NOD 小鼠已被明确定义，并且有几个同系系，其中 Idd 基因座来自抗性 菌株已渗入到 NOD 背景上即可获得。 NOD小鼠易患EAE 从而可以利用该资源进一步分析细胞和 导致 EAE 易感性的遗传因素。转基因 TcR 在适当的载体上表达 遗传和同类背景提供了一个精确的工具来识别易感性的机制 位点可能影响自身反应性 T 细胞的发育和功能。然而，目前还没有 TcR 转基因技术。 可用的小鼠品系可在 NOD 背景下产生 EAE。 利用 NOD 背景上可用的同源菌株来进一步了解 影响中枢神经系统自身免疫研究的遗传因素，我们建议： JJ 首先生成一个 TcR 转基因小鼠对 NOD 背景上的 MOG 35-55 具有特异性，因此抗性和 可以测试致脑炎 T 细胞发育的易感性等位基因。 TcR转基因小鼠 还将测试 T 细胞选择、细胞因子产生、自发性和诱导性 EAE。 2|检查 Idd3 基因座调节自我耐受和 EAE 发展的机制。3)。检查 liCTLA-4 剪接变体是否负责 Idd5.1 遗传区间与 对自身免疫性疾病的易感性。 这些研究将补充正在进行的 Idd 基因座对 I 型发育影响的研究 NOD 小鼠患有糖尿病，将加速影响中枢神经系统发育的基因分析 自身免疫。