Dahlman I, Jacobsson L, Glaser A, Lorentzen J C, Andersson M, Luthman H, Olsson T
Neuroimmunology Unit and Rheumatology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden.
J Immunol. 1999 Mar 1;162(5):2581-8.
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-gamma 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.
用含有匀浆脊髓和完全弗氏佐剂（CFA）的乳剂对近交系暗褐鼠（DA）进行免疫接种，可诱发慢性复发性实验性自身免疫性脑脊髓炎（EAE），这是一种与多发性硬化症有许多相似之处的疾病。我们在此报告首次使用该模型在大鼠中进行全基因组搜索，以寻找调节EAE的数量性状基因座。我们在[DA(RT1av1)×BN(RT1n)]F2杂交群体中，在9号染色体上鉴定出一个数量性状基因座Eae4，它与疾病易感性以及脊髓中促炎细胞因子IFN-γ的mRNA表达相关。与RT1n/av1大鼠相比，Eae4对RT1av1 MHC单倍型纯合的大鼠（RT1av1大鼠）的疾病发生率影响更大，这表明Eae4与MHC之间存在相互作用。在Eae4和MHC中的标记处，DA等位基因的纯合性足以引发EAE。因此，Eae4是决定该DA大鼠杂交群体中EAE易感性的主要遗传因素。此外，有证据支持在1、2、5、7、8、12和15号染色体上与EAE表型存在连锁关系。先前已表明12号染色体区域使DA大鼠易患关节炎，2号染色体区域与小鼠的Eae3同源。我们得出结论，Eae4以及可能其他已鉴定的基因组区域含有调节对神经炎性疾病易感性的基因。这些基因的鉴定和功能表征可能揭示多发性硬化症发病机制中的关键事件；了解这些事件对于开发针对该疾病的新疗法可能至关重要。
