Longitudinal linear-epitope profiling of SLE identifies novel antigens associated with disease and disease activity
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Systemic lupus erythematosus (SLE) is characterized by diverse autoantibodies, yet established biomarkers capture only a fraction of autoreactivity. We profiled 1,268 plasma samples from 695 patients with SLE and 301 healthy controls using phage immunoprecipitation sequencing (PhIP-seq). Machine learning identified a reproducible autoreactivity signature that discriminated SLE from controls across two validation cohorts. SLE autoreactivities were enriched for RNA-binding proteins, while targets containing Basic Acidic Dipeptide repeat domains were associated with high disease activity. A YTHDF2-derived peptide was the most prevalent shared autoreactivity, occurring in ∼25% of patients and exhibiting sequence similarity to Epstein-Barr virus (EBV) lytic switch protein BZLF1. Competition assays demonstrated higher-affinity binding to the viral peptide, consistent with EBV-associated molecular mimicry. Orthogonal validation using a 10-peptide Luminex panel strongly discriminated SLE from healthy controls. These findings expand the SLE autoantibody landscape, identify disease activity associated autoreactivities and insight linking EBV-driven immunity to epitope-specific autoimmunity in lupus.
Authors: Charlotte Hurabielle, Yutong V. Wang, Bryan Castillo-Rojas, Chung-Yu Wang, Colette Caspar, James Asaki, Monica Dayao, Max Calcoen, Eric D. Merrill, Aaron Bodansky, Arielle Klepper, Elizabeth N. Chung, Caroline Vissers, Kelsey C. Zorn, Mark S. Anderson, Michael R. Wilson, Peter Izmirly, Jill Buyon, Jinoos Yazdany, Maria Dall’Era, Chun J. Ye, Joseph L. DeRisi
Institutions: University of California, San Francisco, Chan Zuckerberg Biohub San Francisco, Gladstone Institutes, San Francisco VA Medical Center, University of California San Francisco Medical Center, New York University, San Francisco General Hospital, Genentech, Parker Institute for Cancer Immunotherapy
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vertex Pharmaceuticals, Immune Tolerance Network, National Institutes of Health, Centers for Disease Control and Prevention, Genentech, University of California, San Francisco, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1813425171, RACIAL/ETHNIC AND SOCIOECONOMIC DISPARITIES IN BIOLOGIC AND CLINICAL SLE OUTCOMES, G3862158614, Autoimmune Encephalitis - Ataxia and Psychiatric Disease: Identifying and Characterizing Novel Antibody Targets, G8463206173, HEALTH: HARNESSING EPIDEMIOLOGY TO ADVANCE LUPUS TREATMENT AND HEALTH, Mapping the cell-type-specific molecular and genetic basis of lupus using single cell multiomics, Immune Tolerance Network, Identifying mechanisms of immune dysregulation via severe pediatric SARS-CoV-2, RESOURCE-BASED CENTER FOR THE ADVANCEMENT OF PRECISION MEDICINE IN RHEUMATOLOGY, Academic Rheumatology and Clinical Immunology
OpenAlex ID: W7219645783