Characterization of Y-linked Autoimmune Accelerator Yaa

描述（由申请人提供）：系统性红斑狼疮（SLE）的易感性具有遗传成分，然而，导致该综合征发生和进展风险的复杂遗传变异仍然知之甚少。SLE小鼠模型继续为这种复杂疾病综合征的遗传和表型病因学提供关键见解。其中，BXSB。Yaa小鼠模型从遗传和疾病的角度来看都很有趣。BXSB。由于bxsb背景sle易感等位基因与y染色体相关的自身免疫加速位点（Yaa）之间的上位性相互作用，Yaa雄性小鼠发展出相当严重的自身免疫综合征。这最终导致严重的自身免疫，导致急性肾功能衰竭死亡。可以说，Yaa是在小鼠中发现的最重要的SLE危险因素，也是最棘手的。Yaa通过其对b细胞活化的内在作用，可能通过降低抗原受体依赖性刺激的阈值，显著增强了针对自身抗原的整体自身免疫反应。通过基因、基因组、转录和功能分析的结合，我们已经确定了一个非常强的Yaa候选基因。中线1 （Midin）通常位于X染色体的假常染色体边界附近。其蛋白通常与细胞增殖和分化有关，已被证明与b细胞受体相关信号蛋白Igbpl结合，并与雷帕霉素敏感信号通路相互作用。我们发现，在雄性Yaa小鼠中，这种b细胞激活的正调节因子通过染色体间易位事件从X染色体转移到Y染色体。这种被命名为Midy的重复导致雄性Yaa小鼠中Midin转录表达的整体升高。我们的总体假设是，Midin在Yaa染色体上的转位解释了Yaa表型。从机制上讲，我们提出由这种易位引起的Midin表达升高通过降低通常抑制主要细胞激酶作用的磷酸酶活性而导致b细胞过度活跃。我们将(1)基因组表征Midy的结构，(2)确定转基因升高的Midin表达对b细胞信号传导和自身免疫的影响，以及(3)灭活Midy以评估其产生Yaa表型的潜力。这些研究将阐明Midin影响导致小鼠和人类SLE发病的b细胞信号通路的分子机制。与公共卫生有关。SLE是所有自身免疫性疾病中预测和有效治疗最具挑战性的疾病之一。小鼠模型可用于了解遗传如何影响这种疾病，预测遗传易感性，并确定治疗靶点。我们已经确定了小鼠SLE的一个关键基因。了解它将为人类SLE综合征提供实质性的见解。

DESCRIPTION (provided by applicant): Susceptibility to systemic lupus erythematosus (SLE) has a genetic component, however, the complex genetic variation that results in risk for initiation and progression of this syndrome remains poorly understood. Mouse models for SLE continue to provide key insights into the genetic and phenotypic etiology of this complex disease syndrome. Among them, the BXSB.Yaa mouse model is intriguing both from a genetic and disease perspective. BXSB.Yaa male mice develop a quite severe autoimmune syndrome as a consequence of epistatic interactions between BXSB-background SLE-predisposition alleles and the Y-chromosome-linked autoimmune accelerator locus (Yaa). This ultimately results in severe autoimmunity, leading to death by acute renal failure. Yaa is, arguably, the most substantial SLE risk factor identified in mice, and also the most intractable. Yaa dramatically enhances overall autoimmune responses against autoantigens through its intrinsic effect on B-cell activation, presumably by decreasing the threshold for antigen receptor-dependent stimulation. Through a combination of genetic, genomic, transcriptional, and functional analyses, we have identified a very strong candidate gene for Yaa. Midline 1 (Midin) normally maps near the pseudoautosomal boundary of the X chromosome. Its protein is normally associated with cell proliferation and differentiation, has been shown to bind to the B-cell receptor associated signaling protein, Igbpl, and interacts with a rapamycin sensitive signaling pathway. We have found that this positive regulator of B-cell activation has been transferred from the X to the Y chromosome by an interchromosomal translocation event in male Yaa mice. This duplication, designated Midy, results in an overall elevation of Midin transcriptional expression in male Yaa mice. Our overall hypothesis is that the transposition of Midin onto the Yaa chromosome explains the Yaa phenotype. Mechanistically, we propose that the elevation of Midin expression caused by this translocation results in B-cell hyperactivity by decreasing phosphatase activity that normally represses action of a major cell kinase. We will (1) genomically characterize the structure of Midy, (2) determine the effect of transgenically elevated Midin expression on B-cell signaling and autoimmunity, and (3) inactivate Midy to evaluate its potential for generating the Yaa phenotype. These studies will clarify the molecular mechanisms by which Midin could impact B-cell signaling pathways generally leading to SLE pathogenesis both in mice and humans. Relevance to public health. SLE is one of the most challenging of all autoimmune disorders to predict and effectively treat. Mouse models can be used advantageously to understand how genetics influence this disease, to predict genetic predisposition, and to identify therapeutic targets. We have identified a key gene for mouse SLE. Understanding it will provide substantial insight into human SLE syndromes.