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。遗传因素在多发性硬化症中的作用是 意义重大。多基因遗传可能是多发性硬化症的特征，而且它有 据估计，1到3个易感基因座将预测不同的 多发性硬化症在研究人群中的发生率。重要的是要 了解易感性的关键基因的性质和影响 但这在任何多基因人类疾病中都是有问题的，因为 总发病率低，多胎家庭数量少，规模小 信息丰富的家族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 可行是因为近交系可以用来控制遗传 异质性甚至多基因表型可以在 遗传水平。虽然这不是一个完美的模型，但具有 已被发现在动物对自身免疫的易感性中起重要作用 事实证明，模型在识别相关基因或途径方面很有用 都可以概括为人类的情况，其病原体是 未知。 我们研究了自交系对EAE易感性的机制和遗传控制 老鼠，目的是阐明为什么某些老鼠品系表现出相对 强烈的抵抗力诱导了这一动物模型的人类多发性 硬化症。我们研究的最终目的是阐明 基因控制自身免疫，并可能扩展到理解 多发性硬化症的遗传性机制我们现在已经确定了遗传标记 这对EAE信息型大鼠品系的基因组筛选是有用的 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修改 (Eaem)基因在大鼠4号和5号染色体的相关片段。我们的结果 已经证明至少有一个基因与EAE易感性有关 F344 EAE抗性和LEW EAE易感大鼠之间的差异；以及 在这一特征上，有三个基因将LER EAE抗性大鼠与卢大鼠区分开来。 我们的结果有力地支持了这样一种假设 对T细胞受体β链复合体起重要作用 对这种自身免疫疾病的抵抗力。在下一个支持期内，我们 建议扩大我们的基因组排除图谱结果以识别其他 Eae-m基因座，以分离包含这些基因的染色体片段 遗传易感基因座，并检测遗传相关基因 存在EAE-(MS-)易感性的一个特征： 髓鞘反应性T细胞对脑源性Th1细胞的极化 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.