Genetic Basis for susceptibility to Experimental Autoimmune Encephalomyelitis

描述(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性和双胞胎研究以及近交系小鼠对EAE易感性的差异都表明这些疾病是由遗传因素引起的，但导致疾病易感性/抵抗力的确切细胞和遗传因素尚未确定。为了确定控制EAE易感性的因素，我们对高敏SJL/J和耐药B10.S小鼠进行了细胞免疫学和遗传学分析，这两种小鼠都是相同的MHC(H-2S)单倍型。在SJL和B10.S小鼠的回交中使用微卫星标记，我们发现了多个与EAE易感性显著连锁的基因座。在其他自身免疫性疾病中也发现了一些相同的基因座，特别是在NOD小鼠的糖尿病中，因此增加了相同的遗传因素或“共同的自身免疫基因”可能导致多种自身免疫性疾病的易感性的可能性。确定遗传位点影响T细胞应答的机制的方法之一是在适当的遗传和同源背景下表达转基因TCRs。然而，目前还没有在NOD背景下发生EAE的TCR转基因小鼠品系。 为了研究我们已鉴定的EAE易感基因与糖尿病T细胞应答基因座之间的关系及其在EAE易感/耐药中的作用，我们建议：1)首先在NOD背景上产生针对MOG 35-55的TCR转基因小鼠，以检测耐药和易感等位基因对脑源性T细胞发育的影响。TCR转基因小鼠还将接受T细胞选择、细胞因子产生、自发和诱发性EAE的测试。21定义导致节点1染色体上同源区间EAE易感性差异的遗传元件，命名为Idd5.2和Idd5.3。由于Idd5.2同源间隔使EAE恶化，而Idd5.3防止EAE的发展，我们建议通过减少间隔(Idd5.2，Idd5.3)并分析其对T细胞反应的影响来确定导致这些影响的遗传因素。2)通过将易感SJL株的单个EAE易感基因导入耐药的B10.S背景，检测EAE和T细胞对髓鞘抗原的增殖反应和细胞因子反应在同源品系中的发育情况。 这些研究将确定两种不同菌株组合对EAE的敏感性和抵抗力差异的细胞和遗传学基础，这可能导致MS的易感基因的识别，并有助于识别导致中枢神经系统炎症和脱髓鞘的机制。

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, however the precise cellular and genetic factors that contribute to disease susceptibility/ resistance have not been identified. To define the factors that control susceptibility to EAE, we performed cellular immunological and genetic analysis of highly susceptible SJL/J and resistant B10.S mice, both of which are of the same MHC (H-2S) haplotype. Using microsatellite markers in a backcross of SJL and B10.S mice, we identified multiple loci that show significant linkage to EAE susceptibility. Some of the same loci have also been identified in other autoimmune diseases particularly diabetes in NOD mice thus raising the possibility that the same genetic elements or "common autoimmune genes" may contribute to the susceptibility to multiple autoimmune diseases. One of the ways by which we can identify the mechanism by which genetic loci affect T cell responses, is to express transgenic TcRs on appropriate genetic and congenic backgrounds. However, there is no TcR transgenic mouse strain available that can develop EAE on the NOD background. To study the relationship between the EAE-susceptibility loci that we have identified and the diabetes loci to the type of T cell response and their role in EAE susceptibility/ resistance, 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. 21 Define genetic elements responsible for the difference in EAE susceptibility in the congenic intervals on NOD chromosome 1, named Idd5.2 and Idd5.3. Since the Idd5.2 congenic interval makes EAE worse and the Idd5.3 protects against the development of EAE, we propose to identify the genetic elements that are responsible for these effects by reducing the intervals (Idd5.2, Idd5.3) and analyzing the effect on T cell responses. 2) Test the development of EAE and T cell proliferative and cytokine responses to myelin antigens in congenic strains of mice that we have generated by introducing individual EAE-susceptibility loci from the susceptible SJL strain onto the resistant B10.S background. These studies will define the cellular and genetic basis for the difference in susceptibility and resistance to EAE in two different strain combinations, which may lead to the identification of susceptibility genes in MS and help in the identification of the mechanisms that contribute to inflammation and demyelination in the CNS.