The Role of Sex in Self Antigen Generation in SLE

性别在 SLE 自身抗原生成中的作用

• 批准号: 7895620
• 负责人: DAVID STEPHEN PISETSKY
• 金额: $ 19.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895620
• 关键词: Affect; Animal Model; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antinuclear Antibodies; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Cell Activation; Binding; Biological Markers; Blood; Cell Death; Cells; Characteristics; DNA; Deposition; Development; Diagnosis; Disease; Estrogens; Event; Female; Gender Role; Generations; Gonadal Steroid Hormones; HMGB1 Protein; HMGB1 gene; Histones; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Investigation; Lead; Lupus; Mediating; Modeling; Molecular; Mus; Necrosis; Nuclear; Nuclear Antigens; Nucleic Acids; Nucleosomes; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Pregnancy; Process; Production; Property; Public Health; Research Personnel; Role; Sepsis; Shock; Systemic Lupus Erythematosus; Testing; Tissues; Woman; Y Chromosome; autoreactivity; base; burden of illness; cytokine; extracellular; fetal; in vitro Model; in vivo; in vivo Model; macromolecule; macrophage; male; men; mouse model; novel; novel strategies; pregnant; public health relevance; research study; response; sex; sexual dimorphism; uptake; Affect; Animal Model; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antinuclear Antibodies; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Cell Activation; Binding; Biological Markers; Blood; Cell Death; Cells; Characteristics; DNA; Deposition; Development; Diagnosis; Disease; Estrogens; Event; Female; Gender Role; Generations; Gonadal Steroid Hormones; HMGB1 Protein; HMGB1 gene; Histones; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Investigation; Lead; Lupus; Mediating; Modeling; Molecular; Mus; Necrosis; Nuclear; Nuclear Antigens; Nucleic Acids; Nucleosomes; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Pregnancy; Process; Production; Property; Public Health; Research Personnel; Role; Sepsis; Shock; Systemic Lupus Erythematosus; Testing; Tissues; Woman; Y Chromosome; autoreactivity; base; burden of illness; cytokine; extracellular; fetal; in vitro Model; in vivo; in vivo Model; macromolecule; macrophage; male; men; mouse model; novel; novel strategies; pregnant; public health relevance; research study; response; sex; sexual dimorphism; uptake

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.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种原型自身免疫性疾病，主要影响年轻女性，并有力地体现了性作为免疫介导疾病的决定因素的重要性。实际上，在自身免疫性和炎症性疾病中，SLE显示出最深刻的男女差异之一。如患者和鼠模型的研究所示，SLE的签名特征是抗核抗体的产生（ANA）。这些抗体与多种核大分子（抗核抗体或ANA）结合，尽管对核小体及其DNA和组蛋白成分的抗体是最有特征的。在SLE中，诱导核抗原反应很可能是从死亡和垂死的细胞中释放出来的，细胞死亡和死细胞清除率决定了这种材料的量。除了推动ANA反应外，死细胞的产物还可以用作警报蛋白，以刺激炎症和促进自动反应性。尽管性别对免疫系统产生了广泛的影响，但其对死亡和垂死细胞的反应的影响（包括释放核抗原）尚不清楚。但是，对性影响对休克和败血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及其特性的影响，我们提出了基本的研究，以阐明生成和清除死亡或垂死细胞的机制，以及将核抗原释放到细胞外环境中。尽管这些机制可能是SLE及其下游影响的自身抗体反应的基础，但它们在女性具有更大疾病负担更大的其他州可能具有一般意义。为了研究这些问题，提出了3个具体目标：具体目的1）阐明体内生成细胞外DNA和HMGB1的性二态性。这些研究将测试性别模型中凋亡和坏死细胞的性别对细胞外DNA和HMGB1产生的影响。具体目标2）阐明性激素对体内和体外模型中细胞外DNA和HMGB1产生的影响。这些研究将性激素对细胞外细胞DNA和HMGB1产生的影响；和特定目的3）评估使用体内模型的自身免疫小鼠中细胞外DNA的表达，包括在怀孕小鼠血液中表达胎儿y染色体DNA，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：这些研究将集中于性别作为SLE发病机理的决定因素的作用。 SLE是一种原型自身免疫性，体现了男性女性在免疫介导的疾病负担中的重要性。这些研究将在动物模型中研究性别对死亡和垂死细胞中核分子释放的影响，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的影响以及沉积在组织中并刺激炎症的免疫复合物的形成。了解这些机制应导致新的诊断和治疗方法，以及与狼疮和其他免疫介导的疾病相关的新型生物标志物的发展。