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*
Neuroimmunology Unit and
Rheumatology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; and
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
The immunization of inbred Dark Agouti (DA) rats with an
emulsion containing homogenized spinal cord and CFA induces chronic
relapsing experimental autoimmune encephalomyelitis (EAE), a disease
with many similarities to multiple sclerosis. We report here the first
genome-wide search for quantitative trait loci regulating EAE in the
rat using this model. We identified one quantitative trait locus on
chromosome 9, Eae4, in a [DA(RT1av1) x
BN(RT1n)]F2 intercross showing linkage to
disease susceptibility and expression of mRNA for the proinflammatory
cytokine IFN-
in the spinal cord. Eae4 had a larger
influence on disease incidence among rats that were homozygous for the
RT1av1 MHC haplotype (RT1av1 rats) compared
with RT1n/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.
Thus, 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 chromosome 2 region is
syntenic to Eae3 in mice. We conclude that
Eae4 and probably the other identified genome regions
harbor genes regulating susceptibility to neuroinflammatory disease.
The identification and functional characterization of these genes may
disclose critical events in the pathogenesis of multiple sclerosis;
understanding these events could be essential for the development of
new therapies against the disease.
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