Diagnostic Utility of Antibodies to Histone Post-Translational Modifications in Lupus in Children
Abstract
Various serum antibodies (Abs) are commonly used for the diagnosis of systemic lupus erythematosus (SLE). Anti-nuclear antibodies (ANA) are used as one of the diagnostic criteria for SLE, but they display poor diagnostic specificity. Anti-DNA and anti-nucleosome antibodies have been reported to fluctuate with renal disease in several studies, but they have suboptimal diagnostic potential. Anti-nucleosome antibodies appear earlier than anti-dsDNA Abs, but it is not known if additional specificities can be detected even earlier. In reality, the antigens that trigger lupus are heavily subjected to a multitude of chemical changes called post-translational modifications (PTM). Ab to nucleosome PTMs in SLE have not been comprehensively studied, and their diagnostic significance remains poorly explored. Current Knowledge Gap 1. The complete repertoire of Abs targeting such chemically modified nucleosomal epitopes is currently a black box. Given that a wide spectrum of such chemical modifications has been reported, it is imperative that we study Abs to these modified nucleosomes in SLE comprehensively because these fine specificities are likely to have diagnostic significance as well as relevance to disease pathogenesis. 2. Unfortunately, previous technological platforms to assay Abs to these modified nucleosomes have suboptimal diagnostic performance. Importantly, a novel 3-dimensional, fluorescent bead-based assay has recently been pioneered by industrial partner, EpiCypher that relieves this bottleneck. This novel platform has enabled the proposed studies. Fiscal Year 2022 Lupus Research Program Focus Areas addressed: Understanding how lupus disease heterogeneity impacts risk of disease, disease presentation, clinical course, and outcomes; using a diverse range of research disciplines including, but not limited to, biopsychosocial studies, personalized medicine, variation in treatment studies, health economics, socioeconomic studies, environmental studies, and epidemiological studies We hypothesize that antibodies targeting such chemically modified nucleosomal epitopes could exhibit superior diagnostic potential and pathogenic relevance in lupus. The objective of this academia-industry partnership is to test this hypothesis using a novel, high-throughput, fluorescent bead-based platform bearing a comprehensive battery of chemically modified nucleosomes/histones and several well-annotated SLE cohorts. Research Strategy: Two Aims Are Proposed Aim 1: In this Aim, we propose to identify novel autoantibodies to chemically modified nucleosomes, using two newly designed 50-plex nucleosomes antigen panels. Aim 2: To validate the diagnostic utility of autoantibodies to selected histone/nucleosomal post-translational epitopes using an extended cohort of SLE/LN patients and disease controls. This includes the testing of serum from patients before the diagnosis of lupus. The impact of this Idea Award include the identification of novel autoantibodies (and custom Luminex test panels) that could be of potential utility in the following clinical settings: (i) antibodies that best discriminate pre-SLE and/or SLE from HC with high sensitivity; potential utility: initial or early diagnosis of SLE in someone who does not yet meet all classification criteria for SLE, (ii) antibodies that best discriminate SLE from rheumatic disease controls with high specificity; potential utility: accurate initial diagnosis of SLE, (iii) antibodies that best discriminate active LN from inactive SLE and active nonrenal SLE; potential utility: identification of renal involvement in a patient with SLE, (iv) autoantibodies that correlate strongly with disease activity; potential utility: monitoring SLE/LN patients during follow-up for oncoming changes in disease activity, including renal flares, and (v) autoantibodies that correlate strongly with concurrent renal pathology; potential utility: non-invasive assessment of renal pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310367
Entities
People
- Chandra Mohan
Organizations
- United States Army
- University of Houston