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Principal Investigator: CHANDRA MOHAN
Organization: UNIVERSITY OF HOUSTON
Fiscal Year: 2024
Award: $174,892
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <2-dimensional><3-D><3-Dimensional><3D><Academia><Acetylation><Anti-Smith><Antibodies><Antigenic Determinants><Antigens><Antinuclear Antibodies><Antinuclear Factors><Apoptotic><Assay><Autoantibodies><Autoimmune Diseases><Binding Determinants><Bioassay><Biological Assay><Biological Markers><Black Box><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Cell Body><Cells><Chromatin><DNA><Deoxyribonucleic Acid><Diagnosis><Diagnostic><Diagnostic Specificity><Disease><Disorder><Early treatment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Exhibits><Flare><Goals><Histones><Individual><Industrialization><K12><K12 Award><K12 Mechanism><K12 Program><Kidney><Kidney Urinary System><Knowledge><Lupus><Lupus Erythematosus Disseminatus><Lupus Glomerulonephritis><Lupus Nephritis><Marrow Neutrophil><Mentored Clinical Scientist Development Program><Methylation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nucleosomes><Outcome><Pathogenesis><Pathogenicity><Patients><Peptides><Performance><Physiologic><Physiological><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Protein Modification><Recombinants><Reporting><Research><SLE><Scanning><Sensitivity and Specificity><Serum><Specificity><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><Testing><Validation><accurate diagnosis><anti-DNA autoantibody><anti-Sm><anti-dsDNA antibodies><anti-dsDNA antibody><anti-dsDNA autoantibody><antiDNA autoantibody><antinuclear autoantibody><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><bio-markers><biologic marker><biomarker><cohort><diagnostic ability><diagnostic capability><diagnostic criteria><diagnostic power><diagnostic utility><diagnostic value><disease control><disorder control><disseminated lupus erythematosus><early therapy><epigenetically><extracellular><histone methylation><immunogen><improved><industrial partnership><industry partner><industry partnership><innovate><innovation><innovative><neutrophil><novel><pilot test><renal><screening><screenings><self reactive antibody><systemic lupus erythematosis><three dimensional><two-dimensional><validations>