We're seeking to find out why defects in the gene coding for a protein inside immune cells (ABIN-1) are a risk factor for lupus. Our work will establish whether this protein has potential as a new drug target in lupus.
Human genetic studies have identified TNIP1 as a susceptibility locus for systemic lupus erythematosus (SLE). TNIP1 encodes the protein ABIN-1 (A20 binding inhibitor of NFκB-1), which was originally identified as binding to the ubiquitin-modifying enzyme A20, another SLE associated risk gene. Our hypothesis is that ABIN-1 regulates homeostatic signals that prevent autoimmunity. To dissect the functions of ABIN-1 in autoimmunity, we generated conditional ABIN-1 knockout mice in which ABIN-1 is specifically deleted in dendritic cells. We discovered that ABIN-1 expression is required for maintaining tolerance and protection against autoimmunity. We will test the cellular and molecular regulatory pathways that are disrupted in dendritic cells and in the mice. We will also ask how ABIN-1 collaborates with A20 to prevent SLE. These studies aim to validate ABIN-1 as a true susceptibility gene for SLE and reveal cellular and molecular insights into how ABIN-1 might contribute to SLE risk, providing new opportunities for targeting new therapeutics.