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。该疾病具有复杂的发病机制，涉及免疫系统的许多方面，包括获得性和先天性。SLE在女性中比男性更常见，90%的患者是女性。在青春期前发病的患者以及绝经后的老年患者中，该病存在性别偏见。性激素在已确诊的SLE患者中均异常，但在诊断SLE时，在治疗前，雌激素、雄激素或催乳素均无异常。PI生成的数据显示，与一般人群相比，Klinefelter综合征（男性47岁，XXY）在SLE男性中的比例高出15倍。此外，这些数据表明Klinefelter男性与女性有相同的SLE风险。因此，基于这些数据，PI提出了SLE的X染色体基因效应，这是SLE性别偏见的新假设。新的数据支持这一观点。我们发现，47，XXX存在于8/245例SLE患者中，而47，XXX存在于1/1000例活产女婴中。47，XXX的女性在性激素、月经初潮、怀孕和绝经方面表现正常。因此，这些数据有力地支持了这样的假设，即增加X染色体数量会增加SLE的风险，而不考虑性激素。基于这些数据，我们假设X染色体上的一个基因使具有两个X染色体的人无论性别都有SLE的风险，并且具有三个X染色体的女性患SLE的风险更高。事实上，基于人和小鼠的X失活模式以及新的初步数据，我们已经确定了X染色体上的一个基因，DDX 3X作为X染色体剂量效应的可能介质。DDX 3X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分。该途径与内体中的toll样受体依赖性途径平行，但独立于内体中的toll样受体依赖性途径，内体也识别核酸，产生干扰素并参与狼疮发病机制。初步数据表明，DDX 3X蛋白在具有两个X染色体的人中过表达，而在具有一个X染色体的人中过表达。此外，女性通过DDX 3X途径产生的干扰素高于男性。DDX 3X将作为X染色体剂量效应的介质进行检测。首先，我们将定义人类免疫细胞和小鼠组织中的DDX 3X水平。在具体目标2中，我们将确定女性与男性之间DDX 3X介导的差异干扰素产生。在最后的具体目标中，我们将全面研究DDX 3X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.