Characterization of the Y-linked Autoimmune Accelerator Yaa

描述(由申请人提供)：系统性红斑狼疮(SLE)的易感性有遗传成分，然而，导致这种综合征发生和发展风险的复杂基因变异仍然知之甚少。系统性红斑狼疮的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的见解。其中，BXSB.Yaa小鼠模型从遗传学和疾病的角度都很耐人寻味。BXSB背景的SLE易感等位基因与Y染色体连锁的自身免疫加速器基因(YaA)之间的上位性相互作用导致BXSB.Yaa雄性小鼠发生相当严重的自身免疫综合征。这最终会导致严重的自身免疫，导致急性肾功能衰竭死亡。可以说，YaA是在小鼠身上发现的最重要的SLE风险因素，也是最难处理的。YaA通过其对B细胞激活的内在作用，极大地增强了针对自身抗原的整体自身免疫反应，可能是通过降低抗原受体依赖刺激的阈值。通过结合遗传、基因组、转录和功能分析，我们已经确定了一个非常强大的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。它的蛋白通常与细胞的增殖和分化有关，已被证明与B细胞受体相关的信号蛋白Igbp1结合，并与雷帕霉素敏感的信号通路相互作用。我们发现，在雄性YAA小鼠中，这种积极的B细胞激活调节因子已经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的复制导致了雄性Yaa小鼠Midin转录表达的全面上调。我们的总体假设是，Midin的转座到Yaa染色体上解释了Yaa的表型。从机制上讲，我们认为这种易位引起的Midin表达的增加导致了B细胞的过度活动，这是通过降低磷酸酶的活性来实现的，而磷酸酶通常会抑制主要细胞激酶的活性。我们将(1)确定Midy的基因组特征，(2)确定转基因高表达的Midin对B细胞信号和自身免疫的影响，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B细胞信号通路的分子机制，通常导致小鼠和人类SLE的发病。与公共卫生的相关性。系统性红斑狼疮是所有自身免疫性疾病中最具挑战性的疾病之一，难以预测和有效治疗。小鼠模型可以有利地用于了解遗传学如何影响这种疾病，预测遗传易感性，并确定治疗靶点。我们已经发现了小鼠系统性红斑狼疮的一个关键基因。了解它将为人类SLE综合征提供实质性的洞察力。

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.