Diagnostic utility of antibodies to post-translationally modified nucleosomes in lupus nephritis

翻译后修饰核小体抗体在狼疮性肾炎中的诊断效用

• 批准号: 10683684
• 负责人: CHANDRA MOHAN
• 金额: $ 15.83万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683684
• 关键词: 3-Dimensional; Academia; Acetylation; Antibodies; Antigens; Antinuclear Antibodies; Apoptotic; Autoantibodies; Autoimmune Diseases; Biological Assay; Biological Markers; Cells; Chromatin; DNA; Diagnosis; Diagnostic; Diagnostic Specificity; Disease; Early treatment; Epigenetic Process; Epitopes; Exhibits; Flare; Goals; Histones; Individual; Industrialization; Kidney; Knowledge; Lupus; Lupus Nephritis; Mentored Clinical Scientist Development Program; Methylation; Nucleosomes; Outcome; Pathogenesis; Pathogenicity; Patients; Peptides; Performance; Physiological; Post-Translational Protein Processing; Recombinants; Reporting; Research; Scanning; Sensitivity and Specificity; Serum; Specificity; Systemic Lupus Erythematosus; Testing; Validation; accurate diagnosis; anti-dsDNA antibodies; cohort; diagnostic criteria; diagnostic value; disorder control; extracellular; histone methylation; improved; industry partner; innovation; neutrophil; novel; pilot test; screening; two-dimensional

Anti-nuclear antibodies (ANA) are used as one of the diagnostic criteria for SLE, but they display poor diagnostic specificity for SLE (~76%), as they are also detected in 20-40% of healthy individuals and are frequently observed in other autoimmune diseases. Anti-DNA and anti-nucleosome antibodies have been reported to fluctuate with renal flares in several studies but they have been sub-optimal in their diagnostic potential. Anti-nucleosome and anti-chromatin antibodies appear earlier than anti-dsDNA Abs, about 4-8 years preceding diagnosis but it is not known if additional autoantibody specificities (with higher sensitivity/specificity values) can be detected even earlier. Ab to post-translationally modified nucleosomes in SLE have not been comprehensively studied, and their diagnostic significance remains poorly explored. The repertoire of ANAs targeting epigenetic, PTM nucleosomal epitopes is currently a black box. Given that activated cells, apoptotic cells, cells undergoing netosis all release PTM-nucleosomes (that may serve as immunogens in SLE), it is imperative that we study Abs to epigenetically modified nucleosomes in SLE comprehensively because these fine specificities are likely to have diagnostic significance as well as relevance to disease pathogenesis. Importantly, a 3-dimensional, spectrally resolved, fluorescent bead- based assay pioneered by our industrial partner relieves this bottleneck. The central hypothesis of this proposal is that autoantibodies to histone/nucleosome PTMs could exhibit superior diagnostic potential and pathogenic relevance in lupus. The goal of this academia-industry partnership is to test this hypothesis using a novel, high-throughput, spectrally resolved, fluorescent bead- based screening platform bearing a comprehensive battery of PTM-nucleosomes/histones and several well-annotated SLE cohorts. The availability of reliable serum biomarkers that can accurately diagnose SLE and renal involvement in SLE can prompt earlier treatment, which has been shown to improve long-term outcome. The identified sub-nucleosomal specificities may also shed light on the pathogenic origins of SLE.

抗核抗体（ANA）是SLE的诊断标准之一，但其表现较差