The Role of Sex in Self Antigen Generation in SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种原型自身免疫性疾病，主要影响年轻女性，并有力地证明了性别作为免疫介导疾病决定因素的重要性。事实上，在自身免疫性疾病和炎症性疾病中，SLE在发生率上显示出最深刻的男女差异之一。如患者和小鼠模型的研究所示，SLE的一个特征是产生抗核抗体（ANA）。这些抗体结合广泛的核大分子（抗核抗体或ANA），尽管核小体及其DNA和组蛋白组分的抗体是最具特征的。在SLE中，诱导反应的核抗原最有可能从死亡和垂死的细胞中释放，细胞死亡和死亡细胞清除的速率决定了这种物质的存在量。除了驱动ANA反应外，死细胞的产物还可以作为警报素刺激炎症并促进自身反应性。虽然性对免疫系统有广泛的影响，但它对死亡和垂死细胞的反应的影响，包括核抗原的释放，尚不清楚。然而，关于性别对休克和脓毒症等疾病的影响的研究表明，雌激素可能调节巨噬细胞功能，从而影响清除过程。为了提供一个平台，以更好地了解性别对核抗原暴露及其特性的影响，我们建议进行基础研究，以阐明死亡或垂死细胞的产生和清除以及核抗原释放到细胞外环境中的机制。虽然这些机制可能是SLE自身抗体反应及其下游效应的基础，但它们在女性疾病负担更大的其他状态中可能具有普遍意义。为了研究这些问题，提出了3个具体目标：具体目标1）阐明细胞外DNA和HMGB 1在体内产生中的性二态性。这些研究将在小鼠模型中测试性别对凋亡和坏死细胞产生细胞外DNA和HMGB 1的影响;具体目的2）阐明性激素在体内和体外模型中对细胞外DNA和HMGB 1产生的影响。这些研究将性激素对细胞外DNA和HMGB 1产生的影响;和具体目的3）使用体内模型评估细胞外DNA在自身免疫小鼠中的表达，包括妊娠小鼠血液中胎儿Y染色体DNA的表达，以确定自身免疫对血液中DNA产生和清除的影响。公共卫生相关性：这些研究将关注性别在SLE发病机制中的决定性作用。系统性红斑狼疮是一种原型自身免疫性疾病，其证实了免疫介导的疾病负担中男女差异的重要性。这些研究将在动物模型中调查性别对死亡和垂死细胞释放核分子的影响，这一事件被认为对狼疮至关重要，因为这些分子对免疫反应以及免疫复合物的形成有影响，这些免疫复合物存款在组织中并刺激炎症。了解这些机制应该会导致新的诊断和治疗方法，以及开发与狼疮和其他免疫介导疾病相关的新生物标志物。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and powerfully exemplifies the importance of sex as a determinant of immune-mediated disease. Indeed, among autoimmune and inflammatory diseases, SLE displays one of the most profound male-female differences in occurrence. As shown in studies of both patients and murine models, a signature feature of SLE is production of antinuclear antibodies (ANA). These antibodies bind to a wide array of nuclear macromolecules (antinuclear antibodies or ANA), although antibodies to nucleosomes and its DNA and histone components are the most characteristic. In SLE, the nuclear antigens inducing responses are most likely released from dead and dying cells, with the rates of cell death and dead cell clearance determining the amount of this material present. In addition to driving ANA responses, products of dead cells can function as alarmins to stimulate inflammation and promote autoreactivity. While sex has widespread effects on the immune system, its impact on the response to dead and dying cells, including the release of nuclear antigens, is not known. Studies on the effects of sex influence on conditions such as shock and sepsis suggest, however, that estrogens may modulate macrophage function and thereby influence the clearance process. To provide a platform to understand better the impact of sex on the exposure of nuclear antigens and their properties, we are proposing fundamental investigation to elucidate the mechanism for the generation and clearance of dead or dying cells and the release of nuclear antigens into the extracellular milieu. While these mechanisms may underlie autoantibody responses in SLE and their downstream effects, they may be of general significance in other states in which women have a greater disease burden. To investigate these issues, 3 specific aims are proposed: Specific Aim 1) To elucidate sexual dimorphism in the in vivo generation of extracellular DNA and HMGB1. These studies will test the influence of sex on the generation of extracellular DNA and HMGB1 by apoptotic and necrotic cells in a mouse model; Specific Aim 2) To elucidate the effects of sex hormones on the generation of extracellular DNA and HMGB1 in in vivo and in vitro models. These studies will the influence of sex hormones on the generation of extracellular cellular DNA and HMGB1; and Specific Aim 3) To assess the expression of extracellular DNA in autoimmune mice using in vivo models including the expression of fetal Y chromosome DNA in the blood of pregnant mice to determine the impact of autoimmunity on the generation and clearance of DNA from the blood. PUBLIC HEALTH RELEVANCE: These studies will focus on the role of sex as a determinant in the pathogenesis of SLE. SLE is a prototypic autoimmune that exemplifies the importance of male-female differences in the burden of immune mediated disease. These studies will investigate in animal models the influence of sex on the release of nuclear molecules from dead and dying cells, an event considered crucial to lupus because of the effects of these molecules on immune responses as well as the formation of immune complexes that deposit in the tissues and stimulate inflammation. Understanding these mechanisms should lead to new approaches to diagnosis and treatment as well as the development of novel biomarkers relevant to both lupus and other immune-mediated diseases.