Novel Neutrophil Autoantigens in Systemic Lupus Erythematosus

系统性红斑狼疮中的新型中性粒细胞自身抗原

• 批准号: 8733422
• 负责人: Kaihong Su
• 金额: $ 29.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733422
• 关键词: Acute; Adaptor Signaling Protein; Affect; American; Antibodies; Antibody Activation; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Binding Proteins; Biological Markers; Blood Cells; Cell Adhesion Molecules; Cell Respiration; Cells; Collection; Complex; Data; Deposition; Disease; Fc Receptor; Frequencies; Genes; Goals; Heart; Host Defense; Human; Immune response; Infection; Inflammatory Response; Injury; Interferons; Invaded; Kidney; Knowledge; Lead; Life; Link; Lung; Lupus; Mass Spectrum Analysis; Mediating; Membrane; Modeling; Molecular; Mus; Natural Immunity; Neutropenia; Neutrophil Activation; Nuclear Antigens; Oral; Organ; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Peptide Hydrolases; Peptides; Phosphotransferases; Preventive Intervention; Production; Protein Disulfide Isomerase; Protein Kinase Inhibitors; Proteins; Proteinuria; Reactive Oxygen Species; Recombinant Antibody; Respiratory Burst; Role; Serum; Signal Pathway; Signal Transduction; Slice; Staging; Systemic Lupus Erythematosus; Testing; Therapeutic Intervention; Tissues; Tyrosine Phosphorylation; Up-Regulation; Viral; bactericide; base; design; extracellular; frontier; inhibitor/antagonist; lupus prone mice; microbial; neutrophil; novel; prevent; protein kinase inhibitor; receptor; response; theories; trafficking

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease affecting about 1.5 million Americans. At the devastating disease stage, abnormal immune response can target and destroy many vital organs. Neutrophils are at the frontier of innate immunity against infections. Neutrophil activation has also been linked to tissue injury in acute infections and autoimmune conditions. Using our collection of recombinant antibodies generated from single B cells of SLE patients, we found that a high frequency of SLE-derived recombinant antibodies bind to and activate neutrophils as examined by degranulation and oxidative burst. In particular, S4Ab2 antibody recognizes membrane bound protein disulfide isomerase (PDI) and also induces strong Ca++ influx and protein tyrosine phosphorylation in neutrophils; S4Ab4 antibody recognizes a novel pattern recognition receptor NLRC5/NOD27 and induces neutrophil extracellular trap (NET) formation. Furthermore, administration of S4Ab2 or S4Ab4 antibodies in NZB/W F1 mice induces kidney damage. Based on these results, we hypothesize that a subset of autoantibodies from SLE patients recognizes neutrophil antigens and activates neutrophils, which contributes to tissue damage in SLE. To test this hypothesis, (1) we will examine a large number of SLE-derived recombinant antibodies to identify autoantibodies that bind to and activate neutrophils. We will use these autoantibodies to identify their cognate antigens and determine if such autoantibodies can be used as biomarkers to predict tissue damage in SLE patients. (2) We will determine if SLE derived anti-neutrophil antibodies activate neutrophils through the classical Fc3 receptor pathway and further dissect their signaling pathways using different protein kinase inhibitors. We will also determine the specific signaling of S4Ab2 and S4Ab4 antibodies upon binding to their cognate antigens on neutrophils. (3) We will determine if SLE-derived anti-neutrophil autoantibodies induce tissue damage in murine lupus models. We will further test whether depletion of neutrophils or blocking of neutrophil activation can prevent the autoantibody-mediated tissue damage in murine models. Results from our studies will identify potential bio-markers for prediction of tissue damage in SLE and also help to develop novel preventive and therapeutic interventions for tissue damage in SLE patients.

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，影响约150万美国人。在毁灭性疾病阶段，异常的免疫反应可以针对并破坏许多重要器官。中性粒细胞处于抵抗感染的先天免疫力的前沿。中性粒细胞的激活也与急性感染和自身免疫条件下的组织损伤有关。使用我们收集的SLE患者单个B细胞产生的重组抗体，我们发现SLE来源的重组抗体高频率地结合并激活中性粒细胞，通过脱颗粒和氧化爆发进行检测。特别是，S4Ab2抗体识别膜结合蛋白二硫键异构酶(PDI)，并诱导中性粒细胞钙离子内流和蛋白酪氨酸磷酸化；S4Ab4抗体识别新的模式识别受体NLRC5/NOD27，并诱导中性粒细胞胞外TRAP(Net)的形成。此外，给NZB/W F1小鼠注射S4Ab2或S4Ab4抗体会导致肾脏损伤。基于这些结果，我们假设SLE患者的一部分自身抗体识别中性粒细胞抗原并激活中性粒细胞，从而导致SLE的组织损伤。为了验证这一假设，(1)我们将检查大量来自SLE的重组抗体，以识别与中性粒细胞结合并激活的自身抗体。我们将使用这些自身抗体来识别它们的同源抗原，并确定这些自身抗体是否可以用作预测SLE患者组织损伤的生物标记物。(2)我们将确定SLE来源的抗中性粒细胞抗体是否通过经典的Fc3受体途径激活中性粒细胞，并进一步剖析其使用不同蛋白激酶抑制剂的信号通路。我们还将确定S4Ab2和S4Ab4抗体与中性粒细胞上它们的同源抗原结合时的特异性信号。(3)我们将确定SLE来源的抗中性粒细胞自身抗体是否会在小鼠狼疮模型中引起组织损伤。我们将在小鼠模型中进一步测试去除中性粒细胞或阻断中性粒细胞激活是否可以防止自身抗体介导的组织损伤。我们的研究结果将确定预测SLE组织损伤的潜在生物标志物，并有助于开发针对SLE患者组织损伤的新的预防和治疗干预措施。