Genetic Basis for Sexually Dimorphic EAE Susceptibility

虽然一段时间以来，人们已经知道多发性硬化症（MS）在女性中比在男性中更常见（2-3:1），但原因尚不清楚。目前的理论表明，男性可能患有不同类型的多发性硬化症和/或表现出更严重的症状，而与女性常见的较轻的复发缓解型疾病相比。据认为，免疫反应，如对感染因子的反应和自身免疫反应，是两性二态的。虽然这些差异可能受到性类固醇的影响，但目前的理论无法解释这样一个事实，即激素水平本身在受影响的男性和未受影响的男性之间，或受影响的女性和未受影响的女性之间不太可能有很大的差异。相反，可能不同的是个体独特的性反应基因的遗传特征。许多重要的免疫基因对性类固醇和性相关可溶性因子的存在（或不存在）非常敏感。此外，其他控制性类固醇转化为免疫活性更强的形式的基因可能对MS的临床病程有重大影响。本研究建议使用对实验性自身免疫性脑脊髓炎（EAE）易感性不同的小鼠进行遗传杂交，以确定在MS和EAE中调节性二型易感性的重要基因。

Although it has been know for some time that multiple sclerosis (MS) is more frequently observed in women than in men (2-3:1), it is not known why. Current theories suggest that men may suffer a different type of MS and/or show more severity in their symptoms as compared to the milder relapsing-remitting disease frequently seen in females. It is thought that immune responses, such as responses to infectious agents and autoimmune reactivity, are sexually dimorphic. While these differences are likely influenced by sex steroids, current theories fail to account for the fact that hormone levels themselves are unlikely to vary widely between affected and non-affected men, or affected and non- affected women. Instead, what is likely to be different is an individual's unique genetic profile of sexually responsive genes. Many immunologically significant genes are quite sensitive to the presence (or absence) of sex-steroids and sex-related soluble factors. Additionally, other genes that control the conversion of sex-steroids into immunologically more active forms could have significant influence on the clinical course of MS. This proposal uses genetic crosses of mice that differ in susceptibility to experimental autoimmune encephalomyelitis (EAE), the best-studied animal model of MS, to identify genes important in their ability to regulate the sexually dimorphic susceptibility see in MS and EAE.