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.
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