Principle Investigator: Leah Kottyan, PhD
Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that affects children and adults. There is a strong genetic component to disease risk for SLE, and our group is focused on understanding how genetic variation in DNA can affect an individual’s risk of developing SLE. There are over 80 established genetic risk locus spread across the genome that increase SLE risk. This study focuses on one in a region of DNA encoding the gene IRF7. IRF7 is a transcription factor that binds DNA and allows cells to respond to specific inflammatory signals by promoting the generation of inflammatory gene products.
We have identified a specific genetic variation that is more common in people with lupus and changes an amino acid in IRF7. We will use inflammatory cells derived from patients with SLE to study this genetic variant. In a chemically induced mouse model of lupus, most of the autoantibody production is IRF7 dependent. All strains of laboratory mice have the lupus non-risk variant of IRF7, so we will create a mouse with the risk IRF7 variant. We will compare the mice with the risk and non-risk SLE IRF7 variant to test the hypothesis that this variant increases lupus-like disease and the promotion of inflammatory gene products such as type I interferon. Our proposed study is important because once we understand why the lupus-associated genetic variation increases lupus risk, we can identify optimal therapeutics targeting the IRF7 signaling pathway.