Genetic Basis for susceptibility to Experimental Autoimmune Encephalomyelitis

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近交系小鼠对EAE的易感性差异表明，这些疾病存在遗传因素，然而，导致疾病易感性/抗性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，我们对高易感的SJL/J和耐药的B10进行了细胞免疫学和遗传学分析。S小鼠，两者具有相同的MHC （H-2S）单倍型。微卫星标记在SJL与B10回交中的应用。S小鼠中，我们发现了多个与EAE易感性有显著联系的位点。在其他自身免疫性疾病，特别是NOD小鼠的糖尿病中也发现了一些相同的基因座，从而提出了相同的遗传元件或“共同自身免疫性基因”可能导致多种自身免疫性疾病的易感性的可能性。其中一种方法，我们可以通过遗传位点影响T细胞反应的机制，是表达转基因tcr在适当的遗传和同源背景。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。

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.