Gender Bias in Lupus: Contribution of Sex Chromosomes

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种自身免疫性疾病，女性发病率高于男性，比例为9:1。在大多数对狼疮易感的脊椎动物中，雌性对狼疮的发展也有偏见：我们发现，即使是化学诱导的狼疮，在其他健康的小鼠品系（SJL）中也表现出雌性偏见。这种性别偏见的根本依据尚不清楚。性激素、性染色体或两者都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激素在SLE发展中的作用。独立于性激素的性染色体X和Y基因的贡献作用一直难以解析。我们利用性染色体补体不同的小鼠（XX vs. XY），而性腺类型相同，来确定性染色体补体的效果。在前期工作中，我们将MF1背景的性染色体信息补体渗入到SJL背景中，产生了XX雌性、睾丸决定因子基因Sry缺乏的XY （XY-）雌性、转基因Sry的XX （XX.Sry）雄性和XY-。Sry男性。我们发现XX性染色体的小鼠(XX和XX。对不起)，与XY（女性为XY-，男性为XY-）相比。更严重的自身免疫性疾病，即自身免疫性脑脊髓炎和前列腺素诱导狼疮。在这些新数据的指导下，我们假设与XY相比，XX性染色体补体更容易患狼疮。在本提案中，我们将检验这一假设，并开始剖析其机制。在Aim 1中，我们将研究具有性染色体信息补体的SJL小鼠对pristane诱导狼疮的更大易感性的机制。在Aim 2中，我们将把Y染色体（因Sry而被删除）和Sry转基因基因插入到遗传上容易患狼疮的NZM.2328菌株的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体对这种自发性狼疮模型的影响。最后，在Aims 3中，我们将产生XO基因型小鼠，以确定在Aims 1和Aims 2中，性染色体对疾病结局和免疫措施的影响是否归因于Y染色体特有的基因而不是X基因的剂量。总之，这些拟议的研究将大大促进对性染色体在狼疮中的作用的理解。当前提案的目标是调查性染色体在自身免疫性疾病（如系统性红斑狼疮）中性别偏见的贡献，这种疾病对女性的影响比男性更频繁，比例为9:1。这项研究的结果不仅有助于我们对狼疮的理解，而且还可能导致确定新的治疗目标。

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.