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，但其对SLE的诊断价值不高。 SLE的诊断特异性（~76%），因为它们也在20-40%的健康个体中检测到， 常见于其他自身免疫性疾病。抗DNA和抗核小体抗体已被 据报道，在几项研究中，随着肾耀斑而波动，但在诊断中， 潜力抗核小体和抗染色质抗体比抗dsDNA抗体出现得早，约4-8 在诊断前3年，但尚不清楚是否有额外的自身抗体特异性（具有较高的 灵敏度/特异性值）甚至可以更早地检测。抗后修饰核小体抗体 在SLE中的作用尚未得到全面研究，其诊断意义仍有待进一步探讨。 靶向表观遗传PTM核小体表位的ANA库目前是一个黑匣子。给定 激活的细胞、凋亡细胞、经历细胞凋亡的细胞都释放PTM-核小体（这可能有助于 作为SLE的免疫原），因此，我们有必要研究SLE中表观遗传修饰核小体的Ab 因为这些细微的特异性可能具有诊断意义， 与疾病发病机制的相关性。重要的是，一个三维的，光谱分辨的，荧光珠- 由我们的工业合作伙伴率先推出的基础分析解决了这一瓶颈。 这一建议的中心假设是，组蛋白/核小体PTM的自身抗体可以表现出 狼疮的上级诊断潜力和致病相关性。这个行业的目标是 合作的目的是使用一种新型的、高通量的、光谱分辨的荧光珠来测试这一假设， 基于筛选平台，该平台承载PTM-核小体/组蛋白的综合电池和几个 注释良好的SLE队列。 可准确诊断SLE和肾脏受累的可靠血清生物标志物的可用性 SLE可以促进早期治疗，这已被证明可以改善长期结果。所识别的 亚核小体特异性也可能揭示SLE的致病起源。