IDENTIFICATION OF AUTOIMMUNE GENES IN LPR/LPR MICE

遗传因素有助于自身免疫性疾病的表达， 老鼠和人类都是。这些基因在很大程度上没有特征;此外， 其基因产物和作用机制尚不清楚。 隐性 突变，lpr，发生在MRL小鼠导致深刻的 淋巴结病伴异常T细胞亚群扩增， 全身性自身免疫病 提出了一种“反向”遗传方法 鉴定LPR基因座的突变或缺陷基因产物， 与lpr相互作用导致肾脏疾病的MRL基因。 述的方法 依赖于确定这些基因的物理位置。 RFLV和 微卫星多态性将被用作两种不同的标记。 对临床至关重要的隐性基因的杂交分离 和血清学疾病。 将对肾脏组织学进行评分 并与基因型分析和自身抗体谱相关。 的 将证实lpr对小鼠Chr 19的定位， 将使用来自流式分选的小鼠Chr 19文库的克隆进行作图， 执行。 最感兴趣的将是定义MRL数量性状 基因座（QTL），易患肾炎。 每个的详细映射 基因组的相关区域将使用可用的克隆进行 定位于特定的染色体片段和克隆可能在 基因组的那个区域。 如有必要， 将产生染色体文库或染色体显微切割文库， 允许鉴定的QTL区域之一的饱和作图。 长 小鼠相关区域的范围限制性位点分析 基因组将被执行。 如果一个或多个自身免疫位点 在小鼠和小鼠之间很大程度上保守的染色体片段内， 人类基因组，这些研究可能会确定染色体位置， 人类“自身免疫基因”。 各种策略，包括使用 染色体跳跃和小鼠酵母人工染色体文库， 除了长范围限制性作图之外，还将用于更精确地 确定关键基因的分子位置， 遗传倾向 与MRL +-/+-小鼠的比较 将有助于确定LPR突变， CBA/KJ，在指定菌株的lpr基因座处具有新突变， CBA/KJ-lpr（cg）.对于其他定位的“自身免疫基因”，候选基因 可能是由它们的染色体位置决定的。 单身的定义 一个易患自身免疫的基因应该能让我们 转化为人类和小鼠疾病的分子基础。

Genetic factors contribute to the expression of autoimmune diseases in both mice and humans. These genes are largely uncharacterized; moreover, their gene products and mechanisms of action are unknown. A recessive mutation, lpr, that occurred in MRL mice results in profound lymphadenopathy with expansion of an unusual subpopulation of T cells and generalized autoimmune disease. A "reverse" genetic approach is proposed to identify the mutant or deficient gene products of the lpr locus and MRL genes that interact with lpr to result in renal disease. The method relies on defining the physical location of these genes. RFLV and microsatellite polymorphisms will be used as markers in two different crosses segregating for the recessive genes that are critical to clinical and serologic disease in these mice. The renal histology will be scored and correlated with the genotype analyses and autoantibody profiles. The localization of lpr to mouse Chr 19 will be confirmed and saturation mapping using clones from a flow sorted mouse Chr 19 library will be performed. Of most interest will be defining the MRL quantitative trait loci (QTL) that predispose to nephritis. Detailed mapping of each relevant region of the genome will be undertaken using available clones localized to the specific chromosome segment and clones likely to be in that region of the genome. If necessary, a subchromosome specific library or a chromosome microdissection library will be generated to allow saturation mapping of one of the identified QTL regions. Long range restriction site analyses of the relevant regions of the mouse genome will be performed. If, as is likely, one or more autoimmune loci are within a chromosomal segment largely conserved between the mouse and human genome, these studies may identify the chromosomal location of human "autoimmune genes". A variety of strategies including the use of chromosome jumping and a mouse yeast artificial chromosome library, in addition to long range restriction mapping will be used to more precisely define the molecular location of the critical gene (s) responsible for genetic predisposition. Comparison with MRL-plus-minus/plus-minus mice will be useful for determining the lpr mutation as will comparison of CBA/KJ with a new mutation at the lpr locus in a strain designated CBA/KJ-lpr(cg) . For other localized "autoimmune genes", candidate genes may be suggested by their chromosomal location. Definition of a single gene that predisposes to autoimmunity should allow fundamental insight into molecular basis for disease in mice and humans.