Integrative omics identify increase of pattern recognition and ubiquitin related signatures specific to ANA+ at risk of SLE individuals 2370

Abstract Description Anti-nuclear autoantibodies (ANA) appear years before SLE classification, however, most healthy ANA+ individuals will never develop clinical illness. We sought to identify molecular profiles driving transitions during preclinical autoimmunity development. Proteomic and transcriptomic profiles for 67 subjects (ANA-, ANA+, ILE; SLE) were assessed, respectively; using Olink Explore HT and CITE-Seq. Signatures specific for disease progression were identified using logistic regression and machine learning models, adjusting for age and genetic ancestry. Subjects were genotyped using the Infinium Global Screening Array. Mitochondrial and intracellular sensing proteins such as MAVS, TAX1BP1, RIGI, ITCH, TRAF3 highly correlated (r2 >0.8) with innate cytokine IL1B in early stages of disease progression, and are associated with Memory T, Th2 (p = 0.02), and Activated B cells (p = 0.005). Moreover, Th2 frequencies are increased in ANA+ and ILE (q = 0.02). In ANA+ individuals, inference of gene regulatory networks revealed increased interactions between pattern recognition proteins driven by MAVS. Additionally, we found alleles in ubiquitin pathway members correlated with altered expression of UBXN2B and TRIM25 in ANA+ and ILE individuals. Those findings are potentially associated with dysregulation of mitophagy in cell type and state specific manner. Identified signatures specific to ANA+ individuals suggest alterations in immune response regulation during early stages of disease development. Funding Sources ADAPTS U01AI176244, MONA LISA U01AI176135, UMAI144292, ORDRCC AR073750, OSCTR GM104938 Topic Categories Computational and Systems Immunology (COMP)