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

基本信息

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
项目类别：
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

项目摘要

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）被用作 SLE 的诊断标准之一，但其表现不佳 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，并且常见于其他自身免疫性疾病。抗 DNA 和抗核小体抗体据报道，在几项研究中，其随着肾耀斑而波动，但它们在诊断方面并不是最佳的潜在的。抗核小体和抗染色质抗体比抗 dsDNA 抗体出现早，大约 4-8 年诊断前数年，但尚不清楚是否存在额外的自身抗体特异性（具有更高的特异性）灵敏度/特异性值）可以更早地被检测到。翻译后修饰核小体抗体 SLE 中的 SLE 尚未得到全面研究，其诊断意义也尚未得到充分探讨。针对表观遗传、PTM 核小体表位的 ANA 目前还是一个黑匣子。给定激活的细胞、凋亡细胞、进行网状分裂的细胞都会释放 PTM 核小体（可能有助于作为 SLE 中的免疫原），我们有必要研究 SLE 中表观遗传修饰核小体的抗体全面地因为这些精细的特异性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 3 维、光谱解析的荧光珠我们的工业合作伙伴首创的基于检测的方法缓解了这一瓶颈。该提案的中心假设是组蛋白/核小体 PTM 的自身抗体可能表现出狼疮的卓越诊断潜力和致病相关性。学术界和工业界的目标合作伙伴关系的目的是使用一种新颖的、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，具有 PTM-核小体/组蛋白的综合电池组和多种注释良好的 SLE 队列。可靠的血清生物标志物可准确诊断 SLE 和肾脏受累 SLE 可以促进早期治疗，这已被证明可以改善长期结果。已确定的亚核小体特异性也可能揭示 SLE 的致病起源。