Sex chromosome aneuploidies in autoimmune disease

自身免疫性疾病中的性染色体非整倍体

• 批准号: 8333009
• 负责人: Robert Hal Scofield
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333009
• 关键词: Additional X Chromosome; Adult; Affect; Age; Age-Years; Androgens; Aneuploidy; Animals; Antigens; Autoimmune Diseases; Autoimmunity; Biology; Birth; Brain; Candidate Disease Gene; Cells; Child; Chronic Disease; Complex; Data; Diagnosis; Disease; Dose; Endosomes; Estrogens; Exposure to; Female; General Population; Genes; Gonadal Steroid Hormones; Heart; Homologous Gene; Hormonal; Human; Immune; Immune system; Incidence; Individual; Interferon-beta; Interferons; Investigation; Joints; Kidney; Klinefelter' s Syndrome; Knock-out; Laboratories; Life; Lung; Lupus; Mediating; Mediator of activation protein; Medical; Menarche; Menopause; Messenger RNA; Military Personnel; Mus; Muscle; Nucleic Acids; Organ; Outcome; Paper; Pathogenesis; Pathway interactions; Patient Care; Patients; Pattern; Persons; Postmenopause; Predisposition; Pregnancy; Pristane; Production; Prolactin; Proteins; Puberty; Publications; Regulation; Research; Risk; Severities; Sex Bias; Sex Chromosomes; Skin; Systemic Lupus Erythematosus; Testing; Time; Tissues; Toll-like receptors; Translating; Turner' s Syndrome; Veterans; Woman; X Chromosome; X Inactivation; base; cell type; chronic autoimmune disease; high risk; male; man; men; mouse model; public health relevance; reproductive; sex; young adult

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. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus, or simply lupus, is a chronic disease in which the immune system attacks various organs, including the skin, joints, muscles, lungs, kidneys, heart, and brain. More than 90% of patients are women. Our research is investigating why lupus has a predilection for women. Rare human medical conditions in which there are additional X chromosomes have been highly informative. Men should have one X and women should have 2. However, men with 2 X chromosomes are at the same lupus risk as women, and women with 3 are at an even higher risk for lupus. So, we think that the risk of lupus is related to the numbe of X chromosomes, not sex. The proposal will investigate this idea, including an attempt to identify the gene responsible for this effect. Lupus is a common illness among otherwise healthy young adults. Thus, lupus is frequently diagnosed among military personnel and leads to a medical discharge in most individuals. There are more than 10,000 patients cared for by the Department of Veterans Affairs who are diagnosed with lupus.

描述（由申请人提供）： 全身性红斑狼疮（SLE）是一种可能影响任何器官的疾病。该疾病具有复杂的发病机理，涉及免疫系统的许多方面，包括获得和先天。在女性中，SLE比男性更为普遍，因为90％的患者是女性。该疾病的性偏见存在于青春期前以及更年期后的年龄较大的患者中。性激素在既定SLE的男性和女性中都是异常的，但是在诊断为SLE时，在治疗之前，雌激素，雄激素或催乳素没有异常。 PI生成的数据表明，与一般人群相比，KlineFelter的综合征（男性47，XXY）在SLE的男性中代表了15倍。此外，这些数据表明KlineFelter男性与女性的风险相同。因此，基于这些数据，PI提出了SLE的X染色体基因效应，这是SLE中发现的性偏差的新假设。新数据支持此概念。我们发现47，XXX在245名SLE女性中有8名中存在，而47，XXX中有1000名活着的女性出生中有1000名。 XXX的女性在性激素，初级，怀孕和更年期方面是表型正常的。因此，这些数据强烈支持以下假设：增加的X染色体数量增加了SLE的额外风险，而无需考虑性激素。基于这些数据，我们假设X染色体上的基因为具有两个X染色体的人带来SLE的风险，而不论性别如何，对三个X染色体的女性的SLE风险更高。实际上，基于人和小鼠的X灭活模式以及新的初步数据，我们已经确定了X染色体上的基因DDX3X是X染色体剂量效应的可能介体。 DDX3X蛋白是识别核酸的细胞质途径的关键成分，并在干扰素的产生中达到顶点。该途径与同样识别核酸，产生干扰素并参与狼疮的发病机理的内体中的Toll样受体依赖性途径与Toll样受体依赖性途径无关。初步数据表明，与一个X染色体相比，患有两个X染色体的人的DDX3X蛋白过表达。此外，与男性相比，女性通过DDX3X途径的干扰素产生更高。 DDX3X将被测试为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。在特定的目标2中，我们将确定由女性与男性介导的DDX3X介导的差异干扰素产生。在最终的特定目标中，我们将全面研究DDX3X在敲除动物中的重要性。 公共卫生相关性： 全身性红斑狼疮或简单的狼疮是一种慢性疾病，其中免疫系统会攻击各种器官，包括皮肤，关节，肌肉，肌肉，肺，肾脏，肾脏，心脏和大脑。超过90％的患者是女性。我们的研究正在调查为什么狼疮对女性有偏见。罕见的人类医学状况在其中还有其他X染色体的信息丰富。男性应该有一个X，而女性应该有2个。但是，患有2 X染色体的男性与女性的狼疮风险相同，而患有3个染色体的男性患狼疮的风险更高。因此，我们认为狼疮的风险与X染色体的数量有关，而不是性别。该提案将调查这一想法，包括试图识别负责这种效果的基因。在其他健康的年轻人中，狼疮是一种常见的疾病。因此，狼疮经常在军事人员中被诊断出，并导致大多数人出院。有10,000多名被诊断为狼疮的退伍军人事务部照顾的患者。