Genetic Basis for Sexually Dimorphic EAE Susceptibility

虽然已经知道多发性硬化症(MS)在女性中比男性更常见(2-3：1)，但原因尚不清楚。目前的理论表明，与女性常见的较轻的复发缓解疾病相比，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。据认为，免疫反应，如对感染性病原体的反应和自身免疫反应，是性二型性的。虽然这些差异可能受性类固醇的影响，但目前的理论未能解释这样一个事实，即受影响和未受影响的男性，或受影响和未受影响的女性之间，激素水平本身不太可能有很大差异。相反，可能会有所不同的是一个人独特的性反应基因遗传图谱。许多具有免疫学意义的基因对性类固醇和与性相关的可溶性因子的存在(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形式的基因可能会对MS的临床病程产生重大影响。这项建议使用对实验性自身免疫性脑脊髓炎(EAE)易感性不同的小鼠的基因杂交来识别在调节MS和EAE中性二态易感性方面的重要基因。EAE是研究最深入的动物模型。

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.