2014 General Immune System Function,Target Identification
Innate immune cell mechanisms controlling inflammation in Lupus
The study and what it means to patients
We found that mice genetically engineered to be missing the protein ABIN1 develop a lupus-like disease with striking similarity to human SLE. Using these mice, we will identify immune system processes that cause disease, allowing us to devise novel targeted therapies for lupus.
We do not yet fully understand how lupus develops, but genetic studies suggest that specific molecules may be important in driving its characteristic inflammation. We are particularly interested in an immune cell protein called ABIN1. We have found that loss of ABIN1 in mice results in a lupus-like disease that is very similar to human lupus. We will use the mice lacking ABIN1 to figure out the detailed processes that lead to the development of lupus including the role of immune cells called neutrophils. We are hopeful that this work will lead to the development of more specific therapies for lupus, which should be safer and more effective than the broadly immunosuppressive treatment options available today.
The pathogenetic mechanisms that drive Systemic Lupus Erythematosus (SLE) are still poorly understood. Recent genome-wide association studies have linked TNIP1, which encodes ABIN1, with SLE. We identified ABIN1 as signaling component of Toll-like receptors (TLRs), and studies of ABIN1-deficient mice revealed a lupus-like inflammatory disease with striking similarity to SLE. Innate immune cells use TLRs physiologically to initiate immune responses by pro-inflammatory mechanisms; however, data from SLE patients indicate that TLR-mediated inflammation may also contribute to disease. We show in this application (i) that disease in ABIN1-deficient mice is mediated via MyD88, the master regulator of TLRs and (ii) that disease proceeds independently of T and Bcells. Thus, this model is uniquely suited to investigate TLR-mediated, innate immune cell mechanisms contributing to inflammation in lupus. Using genetic and biochemical experiments, we propose to define (i) the role of suspected culprits, i.e. TLR7, TLR9 and type I interferons, (ii) the impact of specific ABIN1-target genes, i.e. C/EBP, G-CSF and INOS, (iii) the contribution of neutrophils and (iv) the molecular mechanism of ABIN1-mediated gene regulation. We expect that information obtained will help us to identify pathogenetically important factors that contribute to inflammation, and hopefully identify promising therapeutic targets for SLE.