To define the factors that control susceptibility to experimental autoimmune encephalomyelitis (EAE), the investigators have performed cellular immunological and genetic analyses of highly susceptible SJL/J and resistant B 10.S mice, both of which are of the same MHC (H-2s) haplotype. In contrast to the SJL mice, the B10. mice show a relatively poor T cell proliferative response to encephalitogenic myelin epitopes and also do not produce significant amounts of proinflammatory Thl cytokines (IFN gamma) in response to the myelin autoantigens. By a genetic approach using microsatellite markers and a backcross of SJL and B 10.S mice, they 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 ( common """"""""autoimmune gene(s)"""""""") may contribute to the susceptibility to multiple autoimmune diseases. To directly study the relationship of susceptibility loci between various autoimmune diseases and the role of EAE-susceptibility loci on T cell response and IFN-y production they propose to: 1) study the NOD congenic mice in which susceptibility loci have been replaced at chromosome 3 (Idd 3, 10, 17, 18) and chromosome 4 (Idd9) with intervals from the resistant B6/B 10 mice for the development of diabetes and EAE, and subphenotypes such as inflammation and cytokine production in the target organ. 2) Define by genome wide scan using microsatellite markers the genetic loci that are linked to differences in IFN-gamma production in the SJL and B10.S mouse strains, and determine whether polymorphism in IL-12 (a potent inducer of IFN-gamma) between the two strains is responsible for the difference. 3) Test the development of EAE, T cell proliferation and cytokine response to myelin antigens in the SJL-B 10.S congenic strains of mice that will be generated by introducing individual EAE-susceptibility loci from the SJL mice into B 10.S and by transferring EAE-resistance loci from B 10.S into the SJL background. These studies will define the cellular and genetic basis for the self tolerance and the congenic approach will lead to the identification of gene(s) within the loci responsible for the disease phenotype. Furthermore, using congenic mice with resistance loci that overlap among multiple autoimmune diseases will further determine whether genuine """"""""autoimmune alleles"""""""" exist that effect multiple autoimmune diseases.
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