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.

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