Quantitative Analysis of Serum Autoantibody Repertories in Systemic Lupus Erythematosus

系统性红斑狼疮血清自身抗体库的定量分析

• 批准号: 10053315
• 负责人: Kenneth Michael Smith
• 金额: $ 40.67万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053315
• 关键词: 3-Dimensional; Affect; Affinity Chromatography; American; Antibodies; Antigens; Arthralgia; Autoantibodies; Autoantigens; Autoimmune Diseases; Bioinformatics; Biological Markers; Blood; Blood capillaries; Complex Mixtures; Development; Diagnostic; Disease; Electrophoresis; Enzyme-Linked Immunosorbent Assay; Epitope spreading; Exanthema; Foundations; Goals; Immunoglobulin G; Immunology; Intervention; Label; Lead; Light; Link; Mass Spectrum Analysis; Methods; Monoclonal Antibodies; Organ; Pathogenicity; Patients; Pharmaceutical Preparations; Prevention; Process; Production; Prognosis; Proteins; Proteomics; Recombinants; Research; Research Personnel; Resources; Sampling; Serum; Sjogren' s Syndrome; Symptoms; Systemic Lupus Erythematosus; Testing; Time; Work; advanced analytics; analytical tool; antigen binding; base; bioinformatics tool; biomarker discovery; biomarker identification; biomarker validation; diagnostic platform; human monoclonal antibodies; mortality; novel; pathogenic autoantibodies; pressure; prevent; proteogenomics; systemic autoimmune disease; ultra high pressure

SUMMARY Systemic Lupus Erythematosus (SLE) is a multi-organ, systemic autoimmune disorder, estimated to affect at least 1.5 million Americans. The hallmark of SLE is the production of serum autoantibodies, a unifying feature present in over 99% of untreated patients. Such autoantibodies are directly pathogenic, eventually causing the symptoms of SLE including debilitating joint pain and rashes, followed by organ damage and early mortality. Previous work has shown that autoantibodies begin to accrue months to years before the symptoms of SLE appear which may allow a window for detecting them and starting medications to prevent or at least delay the onset of SLE. These serum autoantibodies, however, consist of a complex mixture in the blood including pathogenic, non-pathogenic, and beneficial antibodies which may number in the millions. While current diagnostic platforms can screen for total autoantibodies during autoimmune disease, finding specific monoclonal autoantibodies linked to the development of SLE is currently impossible. Thus, the lack of capability to directly detect monoclonal, pathogenic, autoantibodies presents a significant barrier in understanding how autoantibodies arise, and there is a critical need to develop advanced analytical tools to characterize these antibodies. Our long-term goal is to understand SLE autoantibody development at the monoclonal level and to develop high diagnostic value autoantibody biomarkers. The overall objective of this proposal to establish a novel integrated proteomics platform that employs two complementary scientific approaches, a quantitative top-down MS approach for autoantibody biomarker discovery, and a top-down proteogenomics sequencing approach for autoantibody biomarker validation and functional characterization. Our proposed top-down autoantibody proteomics platform will be applied to identify intact autoantibody Fab signatures in longitudinal SLE serum samples. As a result, we will provide a first top-down proteomics platform for characterizing SLE autoantibodies at the monoclonal level. Applying it to the analysis of SLE autoantibodies will provide foundations for new strategies in SLE prognosis, intervention, and prevention, and may lead to novel high diagnostic value biomarkers. After development, our top-down autoantibody characterization platform can be easily adapted to other autoimmune diseases such as Sjogren’s Syndrome.

概括 系统性红斑狼疮 (SLE) 是一种多器官、系统性自身免疫性疾病，估计会影响 至少 150 万美国人患有 SLE，其特点是产生血清自身抗体，这是一个共同的特征。 超过 99% 的未经治疗的患者体内存在这种自身抗体，具有直接致病性，最终导致疾病。 SLE 的症状包括使人衰弱的关节疼痛和皮疹，然后是器官损伤和早期死亡。 先前的研究表明，自身抗体在系统性红斑狼疮症状出现前数月至数年就开始积累 出现这可能会提供一个窗口来检测它们并开始药物治疗以预防或至少延迟 然而，这些血清自身抗体由血液中的复杂混合物组成，其中包括 目前，致病性、非致病性和有益抗体的数量可能有数百万。 诊断平台可以在自身免疫性疾病期间筛查总自身抗体，发现特定的抗体 因此，单克隆自身抗体与 SLE 的发展相关目前是不可能的。 直接检测单克隆、致病性、自身抗体的能力在 了解自身抗体是如何产生的，并且迫切需要开发先进的分析工具来 我们的长期目标是了解 SLE 自身抗体的发展。 单克隆水平并开发高诊断价值的自身抗体生物标志物。 建议建立一个新颖的综合蛋白质组学平台，该平台采用两种互补的科学 方法，用于发现自身抗体生物标志物的定量自上而下的 MS 方法，以及自上而下的方法 用于自身抗体生物标志物验证和功能表征的蛋白质基因组测序方法。 我们提出的自上而下的自身抗体蛋白质组学平台将用于识别完整的自身抗体 Fab 因此，我们将提供第一个自上而下的蛋白质组学平台。 用于在单克隆水平上表征 SLE 自身抗体，并将其应用于 SLE 分析。 自身抗体将为 SLE 预后、干预和预防的新策略提供基础， 开发后，我们的自上而下的自身抗体可能会产生新型的高诊断价值生物标志物。 表征平台可以轻松适应其他自身免疫性疾病，例如干燥综合症。