Genome-wide linkage analysis of chronic relapsing experimental autoimmune encephalomyelitis in the rat identifies a major susceptibility locus on chromosome 9

The immunization of inbred Dark Agouti (DA) rats with an emulsion containin g homogenized spinal cord and CFA induces chronic relapsing experimental au toimmune encephalomyelitis (EAE), a disease with many similarities to multi ple sclerosis, We report here the first genome-wide search for quantitative trait loci regulating EAE in the rat using this model. We identified one q uantitative trait locus on chromosome 9, Eae4, in a [DA(RT1(av1)) x BN(RT1( n))]F-2 intercross showing linkage to disease susceptibility and expression of mRNA for the proinflammatory cytokine IFN-gamma in the spinal cord. Eae 4 had a larger influence on disease incidence among rats that were homozygo us for the RT1(av1) MHC haplotype (RT1(av1) rats) compared with RT1(n/av1) rats, suggesting an interaction between Eae4 and the MHC, Homozygosity for the DA allele at markers in Eae4 and in the MHC was sufficient for EAE, Thu s, Eae4 is a major genetic factor determining susceptibility to EAE in this cross of DA rats. In addition, there was support for linkage to phenotypes of EAE on chromosomes 1, 2, 5, 7, 8, 12, and 15, The chromosome 12 region has been shown previously to predispose DA rats to arthritis, and the chrom osome 2 region is syntenic to Eae3 in mice. We conclude that Eae4 and proba bly the other identified genome regions harbor genes regulating susceptibil ity to neuroinflammatory disease. The identification and functional charact erization of these genes may disclose critical events in the pathogenesis o f multiple sclerosis; understanding these events could be essential for the development of new therapies against the disease.