GENETIC RESISTANCE TO EAE

遗传因素控制着个体对各种疾病的易感性， 人类自身免疫性疾病 遗传因素在MS中的作用是 显著 多基因遗传可能是MS的特征， 据估计，1至3个易感位点将预测不同的 研究人群中MS的发生率。 重要的是要 了解易感基因的性质和影响 在MS中，但这在任何多基因人类疾病中都存在问题， 一般发病率低，多发病家庭数少， 信息丰富的家庭和人类的遗传多样性 人口 在动物模型中对这些特征的剖析要多得多 可行，因为近交系可用于控制遗传 异质性甚至多基因表型可以在 基因水平。 虽然这不是一个完美的模型，但遗传基因座 在动物自身免疫易感性中起重要作用 模型被证明在识别相关基因或途径方面是有用的， 是普遍适用于人类的条件，其中病原体是 未知 本文研究了近交系EAE易感性的遗传调控机制 大鼠，目的是阐明为什么某些大鼠品系相对 这种动物模型诱导人的抗性强， 硬化症 我们研究的最终目标是揭示 遗传控制自身免疫，可能扩展到理解 MS的遗传机制。我们现在已经确定了遗传标记 其可用于EAE-信息大鼠品系基因组筛选 并进行了必要的初步基因组排除 映射. 我们现在建议识别和物理映射两个EAE修饰 （Eaem）基因在大鼠4号和5号染色体的相关片段中。 我们的结果 已经表明，至少有一个基因是负责EAE易感性 F344 EAE抗性和LEW EAE敏感大鼠之间的差异;以及 有三个基因将LEREAE抗性大鼠与LEW大鼠区分开来。 我们的研究结果为基因关联的假设提供了实质性的支持， 对T细胞受体β链复合物起重要作用， 抵抗这种自身免疫性疾病 在下一个支持期间，我们 我建议扩展我们的基因组排除作图结果，以确定其他 Eae-m基因座，分离含有这些基因的染色体片段 易感基因位点的同类，并测试同类的 EAE-（MS-）易感性的一个标志性特征的存在： 髓鞘反应性T细胞对致脑炎性Th 1的极化 表型。

Genetic factors govern the susceptibility of individuals to a variety of human autoimmune diseases. The role of genetic factors in MS is significant. Polygenic inheritance likely characterizes MS, and it has been estimated that 1 to 3 susceptibility loci would predict the different rates of MS occurrence in studied populations. It is important to understand the nature and impact of the genes critical for susceptibility in MS, but this is problematic in any polygenic human disease, given the low general incidence, the low number of multiplex families, the small size of informative families and in the genetic diversity of the human population. Dissection of these traits in animal models is much more feasible because inbred strains may be used to control for genetic heterogeneity and even polygenic phenotypes can be understood at the genetic level. While it is not a perfect model, the genetic loci that have been found to be important in susceptibility to autoimmunity in animal models are proving useful in identifying relevant genes or pathways that are generalizable to the human conditions for which etiologic agents are unknown. We study the mechanisms and genetic control of EAE-susceptibility in inbred rats, with the goal of elucidating why certain rat strains show relatively strong resistance to the induction of this animal model of human multiple sclerosis. The ultimate goal of our research is to shed light on the genetic control autoimmunity, with possible extension to understanding the mechanisms of heritability of MS. We have now identified genetic markers that are useful for genomic screening of EAE-informative rat strain combinations and have performed the necessary preliminary genome exclusion mapping. We now propose to identify and physically map two EAE-modifying (Eaem) genes in relevant segments of rat chromosomes 4 and 5. Our results have shown that at least one gene is responsible for the EAE-susceptibility difference between F344 EAE-resistant and LEW EAE-susceptible rats; and three genes distinguish LER EAE-resistant rat from LEW rats for this trait. Our results show substantial support for the hypothesis that genes linked to the T cell receptor beta chain complex play a significant role in resistance to this autoimmune disease. In the next support period we propose to extend our genome exclusion mapping results to identify other Eae-m loci, to isolate the chromosomal segments containing these susceptibility loci in congenics, and to test the congenics for the presence of one hallmark characteristic of EAE-(MS-) susceptibility: the polarization of myelin-responsive T cells to the encephalitogenic Th1 phenotype.