The Role of Sex in Self Antigen Generation in SLE

描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，主要影响年轻女性，有力地例证了性作为免疫介导性疾病的决定因素的重要性。事实上，在自身免疫性和炎症性疾病中，SLE的发病率表现出最深刻的男性和女性差异之一。在对患者和小鼠模型的研究中显示，SLE的一个显著特征是产生抗核抗体(ANA)。这些抗体与广泛的核大分子(抗核抗体或ANA)结合，尽管针对核小体及其DNA和组蛋白成分的抗体是最具特征的。在SLE中，核抗原诱导的反应最有可能是从死亡和死亡的细胞中释放出来的，细胞死亡和死亡细胞清除的速度决定了这种物质的存在数量。除了驱动ANA反应外，死亡细胞的产物还可以起到警报的作用，刺激炎症和促进自身反应。虽然性行为对免疫系统有广泛的影响，但它对死亡和濒临死亡的细胞的反应，包括核抗原的释放，其影响尚不清楚。然而，关于性别影响对休克和脓毒症等条件的影响的研究表明，雌激素可能调节巨噬细胞的功能，从而影响清除过程。为了提供一个更好地了解性别对核抗原暴露及其性质的影响的平台，我们提议进行基础研究，以阐明死亡或濒死细胞的产生和清除以及核抗原释放到细胞外环境的机制。虽然这些机制可能是系统性红斑狼疮自身抗体反应及其下游影响的基础，但在女性疾病负担更大的其他州，它们可能具有普遍意义。为了研究这些问题，提出了三个特定目标：特定目标1)阐明细胞外DNA和HMGB1在体内产生的性别二型性。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HMGB1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HMGB1产生的影响。这些研究将包括性激素对细胞外DNA和HMGB1生成的影响；以及特定目的3)利用体内模型评估自身免疫小鼠细胞外DNA的表达，包括胎儿Y染色体DNA在怀孕小鼠血液中的表达，以确定自身免疫对DNA生成和从血液中清除的影响。公共卫生相关性：这些研究将侧重于性别在SLE发病机制中的决定因素的作用。系统性红斑狼疮是一种典型的自身免疫疾病，说明了男性和女性在免疫介导的疾病负担方面存在差异的重要性。这些研究将在动物模型中调查性别对死亡和濒临死亡的细胞释放核分子的影响，这一事件被认为是狼疮的关键，因为这些分子对免疫反应以及沉积在组织中并刺激炎症的免疫复合体的形成产生影响。了解这些机制将导致新的诊断和治疗方法，以及与狼疮和其他免疫介导性疾病相关的新生物标记物的开发。

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.