IMMUNOREGULATORY LOCI IN ORGAN SPECIFIC AUTOIMMUNITY

实验性变态反应性脑脊髓炎与胰岛素依赖 糖尿病(IDDM)是两种器官特异性自身免疫模型 疾病一直是当代研究的主要焦点 自身免疫力。使用这些模型的研究显著地影响了 耐受性及其发病机制的研究现状 导致疾病。然而，由于器官生理学和抗原 表达，并不是这些研究建立的所有范式都是 适用于其他自身抗原。例如，不太受欢迎的两个 实验性变态反应性炎模型和自身免疫性卵巢 发育不全(AOD)，处于表征遗传学的前沿 易感性和免疫病理学基础的架构 抗病能力。EAO的基因组排除图谱研究导致 认为至少有两类自身免疫性疾病的假说 易感基因：1)特定疾病和/或 交叉，以及2)在多个免疫病理上共享或共同的 中介表型。事实上，Orch3的定位和共定位， 控制自身免疫性炎显性抗性的基因座 此应用程序的焦点是11号染色体上的Idd4，它提供了许多 这一假说的推动力。最近，我们报告了一起类似的 Eae7的共同定位表明这三个基因座可能是相同的 基因或多基因家族中紧密相连的基因。为了测试这一点 分子水平上的假设肯定是这些基因座中的一个 被定位克隆。为此，使用BALB.DBA/2小组 11号染色体同基因小鼠，我们已经物理定位了Orch3基因座 位于11号染色体上，间隔约9 cM(BALB.D2Orch3CT3)。 在本研究中，我们将：1)生成额外的BALB.D2Orch3CT3 重组同源基因小鼠缩小编码支持区间 该基因座的大小可以进行定位克隆(小于1 cM)，以及 2)构建酵母人工染色体(YAC)重叠群 Orch3.

Experimental allergic encephalomyelitis (EAE) and insulin-dependent diabetes mellitus (IDDM) are two models of organ-specific autoimmune disease that have been the main focus of contemporary research in autoimmunity. Studies using these models have significantly influenced the current thinking about tolerance and the pathogenic mechanisms leading to disease. However, because of organ physiology and antigen expression, not all of the paradigms established by these studies are applicable to other self antigens. For example, two less popular models, experimental allergic orchitis (EAO) and autoimmune ovarian dysgenesis (AOD), are at the forefront of characterizing the genetic architecture of the immunopathology underlying susceptibility and resistance to disease. Genome exclusion mapping studies of EAO lead to the hypothesis that there are at least two classes of autoimmune disease susceptibility loci: 1) those specific for a particular disease and/or cross, and 2) those shared or common to multiple immunopathologically mediated phenotypes. In fact, the mapping and co-localization of Orch3, the locus controlling dominant resistance to autoimmune orchitis and the focus of this application, with Idd4 on chromosome 11 provide much of the impetus for this hypothesis. Recently, we have reported a similar co-localization for eae7 suggesting that the three loci may be the same gene or tightly linked genes within a multi-gene family. To test this hypothesis at the molecular level definitively one of these loci must be positionally cloned. Toward this end, using a panel of BALB.DBA/2 chromosome 11 congenic mice, we have physically mapped the Orch3 locus on chromosome 11 to an interval approximately 9cM (BALB.D2Orch3CT3). In this study, we will: 1) generate additional BALB.D2Orch3CT3 recombinant congenic mice to narrow down the support interval encoding the locus to a size amenable to positional cloning (less than 1 cM), and 2) construct a yeast artificial chromosome (YAC) contig encompassing Orch3.