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，女性比男性多发生，比例为9：1。雌性对狼疮发展的偏好也见于大多数遗传性狼疮易感的脊椎动物：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）显示雌性偏好。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SLE发展中的作用。很难剖析性染色体X和Y基因的作用，独立于性激素。我们利用性染色体互补性不同（XX与XY）的小鼠，同时具有相同的性腺类型，以确定性染色体互补性的影响。在初步工作中，我们已经将性染色体的信息性互补物从MF 1原种背景渗入到SJL背景中，以产生XX雌性、睾丸决定因子基因Sry缺陷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性染色体补体（XX和XX.Sry）的小鼠经历更严重的自身免疫性疾病，即自身免疫性脑脊髓炎和降植烷诱导的狼疮。在这些新数据的指导下，我们假设与XY相比，XX性染色体补体赋予狼疮更大的易感性。在本提案中，我们将检验这一假设，并开始剖析其机制。在目的1中，我们将研究机制，赋予更大的敏感性降植烷诱导的狼疮SJL小鼠与性染色体的信息补充。在目标2中，我们将Y染色体（缺失Sry）和Sry转基因渐渗到遗传上狼疮倾向的NZM. 2328菌株中至NlO代。然后，将使用疾病测量（蛋白尿、肌酸酐、血尿素氮和肾脏病理学）、自身抗体和免疫应答来确定性染色体补体对这种自发性狼疮模型的影响。最后，在目标3中，我们将产生XO基因型小鼠，以确定性染色体对目标1和2中疾病结局和免疫措施的影响是否归因于Y染色体特有的基因与X基因的剂量。这些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）的性别偏见中的作用，这些疾病影响女性的频率远高于男性，比例为9：1。这项研究的结果不仅有助于我们了解狼疮，而且还可能导致识别新的治疗靶点。

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.