Genetic Elements that Influence Susceptibility to CNS Autoimmunity

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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.