Averil Ma, MD
The University of California, San Francisco, CA
Linking ABIN-1 to SLE Susceptibility
The Study and What It Means to Patients
"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."
Geneticists are identifying a growing number of genes that are altered in lupus patients. While the majority of these genes are known to be involved in the immune system, in most cases we do not understand how the altered genes carried by lupus patients contribute to their disease. The gene that codes for an immune cell protein known as ABIN-1 is one such mystery in lupus. My group has begun to unlock the secrets of ABIN-1. Based on our early results we suspect that in healthy people this protein acts as a brake on the immune system; when it is missing or defective, immune cells go into overdrive and begin to attack the body's own tissues. Our experiments in mice that lack the ABIN gene are providing the first insight on how defects in ABIN-1 disrupt the immune system, potentially laying the foundation for new drugs that switch on ABIN-1 and thereby help control the immune system in lupus and other autoimmune diseases.
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.
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- B Cells
- Cardiovascular System
- Cell Signaling
- Central Nervous System
- Dendritic Cells
- Environmental Triggers
- Gender Matters
- General Immune System Function
- Human Lupus Biology
- Lupus Pregnancy
- New to Lupus
- New Treatments
- T Cells
- Target Identification
- Why the Lupus Immune System Reacts to Its Own DNA