Sex chromosome aneuploidies in autoimmune disease

描述(由申请人提供)： 系统性红斑狼疮(SLE)是一种可以影响任何器官的疾病。该病的发病机制复杂，涉及免疫系统的许多方面，包括后天免疫和先天免疫。系统性红斑狼疮在女性中比男性更常见，因此90%的患者是女性。这种疾病的性别偏见存在于青春期之前以及绝经后年龄较大的患者中。在确诊为SLE的男性和女性中，性激素都是异常的，但在SLE的诊断中，在治疗之前，没有雌激素、雄激素或催乳素的异常。PI生成的数据显示，与普通人群相比，Klinefelter综合征(男性，47岁，XXY)在SLE男性中的发病率高出15倍。此外，这些数据表明，Klinefelter男性与女性患系统性红斑狼疮的风险相同。因此，基于这些数据，PI提出了SLE的X染色体基因效应，这是对SLE性别偏见的一种新的假设。新的数据支持这一观点。我们发现，在245名SLE妇女中，有8人存在47，XXX，而每1000名活产女婴中就有1人存在47，XXX。有47，XXX基因的女性在性激素、月经初潮、怀孕和更年期方面表现正常。因此，这些数据有力地支持了这样的假设，即增加X染色体的数量会增加SLE的风险，而与性激素无关。基于这些数据，我们假设X染色体上的一个基因，无论性别，都会给有两个X染色体的人带来系统性红斑狼疮的风险，而对三个X染色体的女性来说，系统性红斑狼疮的风险更高。事实上，基于人类和小鼠的X失活模式以及新的初步数据，我们已经确定X染色体上的一个基因DDX3X可能是X染色体剂量效应的中介。DDX3X蛋白是识别核酸并最终产生干扰素的细胞质途径的关键组成部分。这一途径与内体中的Toll样受体依赖途径平行，但独立于该途径，后者也识别核酸，产生干扰素，并参与狼疮的发病。初步数据显示，与具有一条X染色体的人相比，具有两条X染色体的人的DDX3X蛋白过度表达。此外，通过DDX3X途径产生的干扰素在女性中比男性更高。将测试DDX3X作为X染色体剂量效应的介体。首先，我们将定义人类免疫细胞和小鼠组织中的DDX3X水平。在具体目标2中，我们将确定DDX3X介导的女性与男性干扰素产生的差异。在最终的具体目标中，我们将全面研究DDX3X在基因敲除动物中的重要性。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a disease that can affect any organ. The disease has a complicated pathogenesis involving many aspects of the immune system, including acquired and innate. SLE is substantially more common among women than men such that 90% of patients are female. The sex bias of the disease is present in patients with onset before puberty as well as at older ages after menopause. Sex hormones are abnormal in both men and women with established SLE, but at the diagnosis of SLE, prior to therapy, there are no abnormalities of estrogen, androgen or prolactin. The PI has generated data showing that Klinefelter's syndrome (male 47,XXY) is 15-fold over-represented among men with SLE compared to the general population. In addition, these data indicate that Klinefelter men are at the same risk of SLE as women. Therefore, based on these data, the PI has proposed an X chromosome gene effect for SLE, which is a new hypothesis for the sex bias found in SLE. New data support this notion. We find that 47,XXX is present in 8 of 245 women with SLE, while 47,XXX is present in 1 in 1000 live female births. Women with 47,XXX are phenotypically normal in terms of sex hormones, menarche, pregnancy and menopause. Thus, these data strongly support the hypothesis that increasing number of X chromosomes imparts additional risk of SLE without regard to sex hormones. Based on these data we hypothesize a gene on the X chromosome that gives a risk of SLE to persons with two X chromosomes regardless of sex, and an even higher risk of SLE to women with three X chromosomes. In fact, based on X inactivation patterns in man and mouse as well as new preliminary data, we have identified a gene on the X chromosome, DDX3X as a possible mediator of the X chromosome dose effect. The DDX3X protein is a critical component of a cytoplasmic pathway that recognizes nucleic acids, and culminates in production of interferon. This pathway is parallel with, but independent of the toll-like receptor-dependent pathway in the endosome that also recognizes nucleic acid, produces interferon and is involved in lupus pathogenesis. Preliminary Data indicate the DDX3X protein is over-expressed in persons with two X chromosomes compared to those with one X. Furthermore, interferon production through the DDX3X pathway is higher in woman compared to men. DDX3X will be tested as the mediator of the X chromosome dose effect. First, we will define DDX3X levels in human immune cells and mouse tissues. In Specific Aim 2, we will determine differential interferon production as mediated by DDX3X by women versus men. In the final Specific aim, we will comprehensively study the importance of DDX3X in knock-out animals.