A Genome-Wide Search Identifies Two Susceptibility Loci for Experimental Autoimmune Encephalomyelitis on Rat Chromosomes 4 and 10

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that exhibits many pathologic similarities with multiple sclerosis. The genetic loci that contribute to mononuclear cell infiltration of the central nervous system and clinical manifestations of EAE in the rat were investigated in the F2 progeny of the highly susceptible Lewis and resistant Brown Norway strains. The data confirmed that the Lewis allele of a MHC-linked gene is necessary, but not sufficient, to confer EAE susceptibility in the F2 progeny. Subsequent analyses were thus restricted to the subset of the F2 animals with EAE-predisposing MHC genotypes. A genome-wide scan approach was performed using 103 microsatellite markers covering 85% of the genome. Two non-MHC regions were identified, one near the centromere of chromosome 4 and the other on the long arm of chromosome 10, that significantly contributed to the disease. In addition, three regions on chromosomes 9, 13, and 17 were suggestive for linkage. Congenic mapping is now needed to reduce the support intervals encoding the loci of interest to sizes amenable to physical mapping and to eventually demonstrate the involvement of some of the candidate genes of immunologic importance localized in these regions.