Gender Bias in Lupus: Contribution of Sex Chromosomes

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，女性比男性更多地发生，比例为9：1。女性对狼疮的发展也有偏见，在大多数遗传易感狼疮的脊椎动物中也可以看到：我们发现，即使是在其他健康的小鼠品系(SJL)中，即使是化学诱导的狼疮也表现出雌性偏见。这种性别偏见的根本基础仍然不清楚。性激素、性染色体或两者都有可能导致这种性别差异。广泛的人类和动物研究已经调查了性腺激素在系统性红斑狼疮发展中的作用。很难剖析性染色体X和Y基因的贡献作用，而不依赖于性激素。我们利用性腺类型相同但性染色体组成不同的小鼠(XX和XY)来确定性染色体互补的影响。在前期工作中，我们已经将MF1群体中的性染色体的信息互补引入到SJL背景中，产生了XX雌性、睾丸决定因子基因Sry缺失的XY(XY-)雌性、Sry转基因XX(XX.Sry)雄性和XY-Sry雄性。我们已经发现，与XY(雌性XY-和雄性XY-.Sry)相比，XX性染色体互补(XX和XX.Sry)的小鼠经历了更严重的自身免疫性疾病，即自身免疫性脑脊髓炎和Pristane诱导的狼疮。在这些新数据的指导下，我们假设，与XY相比，XX性染色体互补赋予狼疮更大的易感性。在这个提案中，我们将检验这一假说，并开始剖析其机制。在目标1中，我们将通过性染色体的信息补充来研究在SJL小鼠中赋予Pristane诱导的狼疮更大的易感性的机制。在目标2中，我们将Y染色体(Sry缺失)和Sry转基因导入易患狼疮的NZM.2328菌株到N10代。然后，将通过疾病测量(蛋白尿、肌酐、血尿素氮和肾脏病理)、自身抗体和免疫反应来确定性染色体补充对这个自发的狼疮模型的影响。最后，在目标3中，我们将产生XO基因型的小鼠，以确定目标1和2中的性染色体对疾病结局和免疫措施的影响是否可归因于Y染色体特有的基因与X基因的剂量。总之，这些拟议的研究将极大地促进对性染色体在狼疮中作用的理解。公共卫生相关性目前的建议的目标是研究性染色体在自身免疫性疾病(如系统性红斑狼疮)中的性别偏见中的作用，这些疾病影响女性的频率比男性高得多，比例为9：1。拟议的研究结果不仅有助于我们对狼疮的理解，还可能有助于确定新的治疗靶点。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs more in females than males at a ratio of 9:1. The female bias for the development of lupus is also seen in most genetically lupus-susceptible Vertebrate Animals: We have found that even chemically induced lupus in an otherwise healthy mouse strain (SJL) displays a female bias. The fundamental basis for such gender bias remains unclear. Sex hormones, sex chromosomes or both may contribute to such sex difference. Extensive human and animal studies have investigated the role of gonadal hormones on the development of SLE. It has been difficult to dissect the role of contribution of sex chromosome X and Y genes, independent of sex hormones. We have made use of mice that differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex chromosome complements. In preliminary work, we have introgressed the informative complement of sex chromosomes from the stock MF1 background onto the SJL background to generate XX females, testes determining factor gene Sry-deficient XY (XY-) females, and Sry transgenic XX (XX.Sry) males, and XY-.Sry males. We have found that mice of the XX sex chromosome complement (XX and XX.Sry), as compared to XY (female XY- and male XY-.Sry), experience more severe autoimmune disease, namely autoimmune encephalomyelitis and pristane-induced lupus. Guided by these novel data, we hypothesize that XX sex chromosome complement, as compared to XY, confers greater susceptibility to lupus. In this proposal, we will test this hypothesis and begin to dissect the mechanisms. In Aim 1, we will investigate mechanisms that confer greater susceptibility to pristane-induced lupus in SJL mice with the informative complement of sex chromosomes. In Aim 2, we will introgress the Y- chromosome (deleted for Sry) and the Sry transgene onto the genetically lupus-prone NZM.2328 strain to the N10 generation. Then, the effect of sex chromosome complement on this spontaneous model of lupus will be ascertained using disease measures (proteinuria, creatinine, blood urea nitrogen and renal pathology), autoantibodies and immune responses. Finally, in Aim 3, we will generate mice of the XO genotype to determine if the sex chromosome effect on disease outcomes and immune measures in Aims 1 and 2 is attributable to a gene unique to the Y chromosome versus the dosage of X genes. Together these proposed studies will greatly advance the understanding of the role of sex chromosomes in lupus. PUBLIC HEALTH RELEVANCE The goal of the current proposal is to investigate the contribution of sex chromosomes in the gender bias in autoimmune diseases such as systemic lupus erythematosus, which affect women much more frequently than men with a ratio of 9:1. The results of the proposed study will not only aid our understanding of lupus, but will also potentially lead to identification of newer targets of treatment.