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)是系统性红斑狼疮的诊断标准之一，但表现不佳 对SLE的诊断特异性(~76%)，因为它们也在20%-40%的健康人中检测到，并且 常见于其他自身免疫性疾病。抗DNA和抗核小体抗体已经被 据报道，在几项研究中，肾红斑会随之波动，但它们在诊断上并不理想 潜力。抗核小体和抗染色质抗体比抗dsDNA抗体出现得更早，约为4-8 诊断前几年，但尚不清楚是否有更多的自身抗体特异性(具有更高的 敏感度/特异度)甚至可以更早地检测到。AB到翻译后修饰的核小体 系统性红斑狼疮的发病机制尚未得到全面研究，其诊断意义仍未得到充分探讨。 以表观遗传的PTM核小体表位为靶点的全套ANA目前是一个黑匣子。vt.给出 激活的细胞、凋亡的细胞、网状分裂的细胞都会释放PTM-核小体(这可能是 作为SLE的免疫原)，对SLE表观遗传修饰核小体的抗体研究势在必行 因为这些细微的特异性很可能具有诊断意义以及 与疾病发病机制的相关性。重要的是，一个三维的，光谱分辨率的，荧光微珠- 由我们的工业合作伙伴率先开发的基于测试的方法缓解了这一瓶颈。 这一提议的中心假设是抗组蛋白/核小体PTMS的自身抗体可能表现出 狼疮具有较高的诊断潜力和致病相关性。这个学术界和产业界的目标 合作伙伴关系将使用一种新型的、高通量、光谱分辨率的荧光微珠来验证这一假设- 基于筛选平台，携带PTM-核小体/组蛋白和几个 注释良好的系统性红斑狼疮队列。 能准确诊断系统性红斑狼疮和肾脏损害的可靠血清生物标志物的可用性 系统性红斑狼疮可以促使早期治疗，这已被证明可以改善长期结果。被识别的人 亚核小体的特异性也可能揭示SLE的致病来源。