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，涉及免疫系统的许多方面。在SLE和SS中存在强烈的性别偏见，女性比男性多10倍。在男性和女性SLE患者中，性激素异常。然而，在诊断SLE时，在治疗之前，无论发病年龄如何，都没有异常。PI报告称，与一般或对照人群相比，Klinefelter综合征（男性47岁，XXY）在SLE和SS男性中的比例分别高出15倍和38倍。这些数据和使用贝叶斯定理的计算表明，克兰费尔特男性至少与女性有相同的SLE和SS风险。因此，基于这些数据，PI提出了SLE和SS的X染色体基因效应，这是在这些疾病中发现的性别偏见的新假设。其他新数据也支持这一观点。我们发现47，XXX在女性SLE（7/2826）和SS（3/1033）患者中统计学增加，与对照组（2/7074）相比。我们发现原发性胆汁性肝硬化和RA受试者中47，XXX没有增加，这两种受试者都有女性偏倚，表明性别偏倚的替代机制。47，XXX的女性在性激素、月经初潮、怀孕和绝经方面表现正常。在XX和XY雌性以及XX和XY雄性小鼠中进行的SLE研究的数据也强烈支持以下假设，即X染色体数量增加会增加SLE/SS的风险，而不考虑性激素。基于PI生成的数据以及这些小鼠数据，我们假设在人和小鼠中逃避X失活的X连锁基因DDX 3X、CXorf 38、KDM 6A、KDM 5C CA 5 B EIF 2S 3可能导致具有2条或更多X染色体的人（无论性别如何）SLE或SS风险增加。我们提出的研究将是第一个研究正常男性和女性与那些有X染色体的人之间逃避X失活的基因的差异基因和蛋白质表达。新的初步数据支持DDX 3X和CXorf 38（一种未表征的基因和蛋白质产物）作为X染色体剂量效应的可能介质，因为我们发现两种蛋白质的表达与X染色体数目相关。DDX 3X蛋白是识别核酸的细胞质途径的关键组分，并在干扰素产生中达到高潮。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SLE发病机制。此外，女性通过DDX 3X途径产生的干扰素高于男性。初步数据显示，CXorf 38在B细胞中表达，与雄性细胞相比，在雌性细胞中的表达更高，并且该蛋白质可能参与B细胞活化。在特定目标1中，通过定义人免疫细胞和小鼠组织中6种基因的蛋白水平，将DDX 3X和其他5种基因中的每一种作为X染色体剂量效应的可能介质进行检测。在具体目标2，我们将建立一个功能性的作用，差异过表达的X连锁基因在SLE人类受试者和小鼠模型。在最后的具体目标中，我们将在染色体非整倍体小鼠模型中描述诱导性和自发性狼疮的严重程度和易感性。

 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.