Sex chromosome aneuploidies in autoimmune disease

 描述(由申请人提供)： 系统性红斑狼疮(SLE)和干燥综合征(SS)是自身免疫性疾病，其发病机制复杂，涉及免疫系统的多个方面。在SLE和SS中都存在强烈的性别偏见，受影响的女性是男性的10倍。在确诊的SLE男性和女性患者中，性激素都是异常的。然而，在诊断为系统性红斑狼疮时，无论发病年龄如何，在治疗前都没有异常。PI报告称，与普通人群或对照人群相比，Klinefelter综合征(男性47，XXY)在患有SLE和SS的男性中分别高出15倍和38倍。这些数据和使用贝叶斯理论的计算表明，Klinefelter男性患系统性红斑狼疮和SS的风险至少与女性相同。因此，基于这些数据，PI提出了SLE和SS的X染色体基因效应，这是对这些疾病中发现的性别偏见的新假设。更多的新数据支持这一观点。我们发现女性SLE患者(7/2826)和SS患者(3/1033)的47，XXX在统计学上高于对照组(2/7,074)。我们发现，在原发性胆汁性肝硬变和类风湿性关节炎患者中，47，XXX没有增加，这两者都有女性偏见，这表明性别偏见的另一种机制。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。来自XX和XY雌性小鼠以及XX和XY雄性小鼠的SLE研究数据也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/SS的风险，而与性激素无关。基于PI产生的数据以及这些小鼠数据，我们假设在人和小鼠中逃脱X失活的X连锁基因DDX3X、CXorf38、KDM6A、KDM5C CA5B EIF2S3可能会导致具有2条或更多X染色体的人患SLE或SS的风险增加，无论性别。我们拟议的研究将首次检测正常男性和女性以及具有外X染色体的人之间逃脱X失活的基因和蛋白的差异表达。新的初步数据支持DDX3X和CXorf38(一种未鉴定的基因和蛋白产物)可能是X染色体剂量效应的中介，因为我们发现这两种蛋白的表达与X染色体数量有关。DDX3X蛋白是识别核酸的细胞质途径的关键组成部分，最终导致干扰素的产生。这一途径与内体中的Toll样受体依赖途径平行，但不依赖于该途径，后者也识别核酸，产生干扰素，并参与SLE的发病。此外，女性通过DDX3X途径产生的干扰素比男性更高。初步数据显示，CXorf38在B细胞中表达，在女性细胞中的表达高于男性细胞，该蛋白可能参与了B细胞的激活。在具体目标1中，通过确定人免疫细胞和小鼠组织中6个基因的蛋白质水平，将DDX3X和其他5个基因中的每一个作为X染色体剂量效应的可能中介因子(S)进行测试。在特定的目标2中，我们将在SLE受试者和小鼠模型中建立差异过度表达的X连锁基因的功能作用。在最终的特定目标中，我们将在染色体非整倍体小鼠模型中表征诱发和自发性狼疮的严重性和易感性。

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are autoimmune diseases with a complicated pathogenesis involving many aspects of the immune system. There is a strong gender bias in both SLE and SS, with 10 times more women affected than men. In both male and female patients with established SLE, sex hormones are abnormal. However, at the diagnosis of SLE, prior to therapy and regardless of age of onset, there are no abnormalities. The PI has reported that compared to the general or control population, Klinefelter's syndrome (male 47,XXY) is 15-fold and 38-fold over-represented among men with SLE and SS, respectively. These data and calculations using Bayes' theorum indicate that Klinefelter men have at least the same risk of SLE and SS as women. Therefore, based on these data, the PI has proposed an X chromosome gene effect for SLE and SS, which is a new hypothesis for the sex bias found in these disorders. Additional new data support this notion. We find 47,XXX statistically increased in female SLE (7 of 2826) and SS (3 of 1,033) patients, as compared to controls (2 of 7,074). We found no increase in 47,XXX in primary biliary cirrhosis and RA subjects, both of which have a female bias, indicating alternative mechanisms for sex bias. Women with 47,XXX are phenotypically normal in terms of sex hormones, menarche, pregnancy and menopause. Data from studies of SLE in mice with XX and XY females as well as XX and XY males also strongly support the hypothesis that increasing number of X chromosomes imparts additional risk of SLE/SS without regard to sex hormones. Based on data generated by the PI as well as these mouse data we hypothesize that X-linked genes that escape X inactivation in both man and mouse, DDX3X, CXorf38, KDM6A, KDM5C CA5B EIF2S3 may cause an increased risk of SLE or SS to persons with 2 or more X chromosomes, regardless of sex. Our proposed study will be the first to examine differential gene and protein expression of genes that escape X inactivation between normal men and women and those with extranumerary X chromosomes. New preliminary data support DDX3X and CXorf38 ( an uncharacterized gene and protein product) as possible mediators of the X chromosome dose effect as we have found correlations of expression in both proteins with X chromosome number. The DDX3X protein is a critical component of a cytoplasmic pathway recognizing nucleic acids, and culminates in interferon production. 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 SLE pathogenesis. Furthermore, interferon production through the DDX3X pathway is higher in woman compared to men. Preliminary Data show that CXorf38 is expressed in B cells, expression is greater in female cells compared to male cells and that this protein may be involved in B cells activation. In Specific Aim 1, DDX3X and each of the other 5 genes will be tested as possible mediator(s) of the X chromosome dose effect by defining protein levels of the six genes in human immune cells and mouse tissues. In Specific Aim 2, we will establish a functional role for differentially overexpressed X-linked genes in SLE human subjects and mouse models. In the final Specific aim, we will characterize severity and susceptibility of induced and spontaneous lupus in a chromosome aneuploidy mouse model.