Antigen-Presentation of Isolevuglandin-modified peptides in hypertension, autoimmunity and target-organ damage

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

PROJECT SUMMARY Emerging evidence has shown that hypertension and its associated target organ damage are in part mediated by inflammation and immune activation. Hypertension is also common in autoimmune diseases including systemic lupus erythematosus (SLE) and psoriasis. Robust experimental and clinical data indicate that Isolevuglandin (IsoLG)-adducted peptides are formed in all these conditions. These IsoLG-adducts are presented by major histocompatibility complexes (MHCs) to activate subsets of T cells and notably CD8+ T cells. Using computational approaches, we screened millions of potential peptides and defined structural characteristics of class I MHCs required for IsoLG-adducted peptide presentation. Using experimental approaches, we discovered 4 such peptides derived from the Sodium Glucose Transporter 2, Cadherin 16, Kelch Domain 7A, and Solute Carrier 23 (SCKS peptides) that are antigenic in hypertension. When IsoLG-adducted and loaded into a fluorescent IgG/H2-Db probe, these peptides bind to up to 15% of T cells in target organs of hypertensive mice and are observed in tissues of mice with experimental psoriasis and in mice with SLE. When loaded into dendritic cells (DCs), these stimulate proliferation of T cells from hypertensive mice. Notably, DCs loaded with IsoLG-adducted SCKS peptides prime hypertension when adoptively transferred to naïve mice. Aim 1 will test the hypothesis that IsoLG-responsive T cells and the antigens that stimulate these are shared between hypertension and autoimmune diseases. In collaboration with Projects 2 and 3, we will determine if the SCKS peptides activate T cells from mice with SLE and psoriasis. We will determine if IsoLG scavenging eliminates the SCKS reactive T cells and will determine if the SCKS-specific T cells prime hypertension to a greater extent than do T cells not recognized by the IsoLG-adducted SCKS peptides. For aim 2, we have developed a score to quantify the capacity of humans to present IsoLG-adducts, termed the ISOPTER score, based on class I HLA allele composition, and have imputed class I HLA composition in 92,000 subjects in our BioVU population. We will determine if the ISOPTER score associates with hypertension, target-organ damage and if it predicts development of disease. A major goal of this aim will be to optimize the ISOPTER score, using machine learning and neural network approaches. Our ISOPTER score will be applied to human subjects studied in Projects 2 and 3 to determine if it predicts responses to IsoLG scavenging. In aim 3, we will test the hypothesis that IsoLG- adducts activate unique T cell receptors (TCRs) in human hypertension and to identify peptide epitopes that activate these TCRs. We will study human analogs of the peptides we have discovered in mice and use a non- biased approach to discover previously unknown peptides that act as antigens in human hypertension. These studies will bring novel molecular approaches and tools to the study of hypertension which will benefit the scientific community in future years. Furthermore, our Project will provide new treatments and biomarkers that will guide therapy of humans with hypertension and autoimmune diseases in which hypertension is prevalent.