In this paper a collaboration between Sambit Nanda in Philip Cohen's lab and David Powell at the University of Kentucky, has led to the discovery that mutations in ABIN1 predispose to a particular form of Systemic Lupus Erythematosus, a serious autoimmune disorder affecting 3.5 million people worldwide. Many different organs of the body can be damaged in different types of lupus, and the new findings have identified mutations in ABIN1 that are associated with kidney damage in lupus patients. These findings may lead to the improved diagnosis and treatment of this disease.
ABIN1 is a polyubiquitin-binding protein that plays an important role in restricting the strength of activation of the MyD88 signaling network in the innate immune system. In an paper published a couple of years ago Sambit Nanda found that knock-in mice in which Asp485 of ABIN1 was mutated to Asn, to generate a a polyubiquitin-binding-defective mutant, developed a lupus-like autoimmune disease. He found that the disease was caused by the hyper-activation of the MyD88-dependent signaling network because it was prevented by crossing the ABIN1[D485N] mice to MyD88 knock-out mice (Nanda et al, 2011, J. Exp. Med. 208, 1215-1228). In the new paper, published on-line on August 22nd in the Journal of the American Society of Nephrology, the ABIN1[D485N] mice were found to develop progressive glomerular nephritis (GN), which closely resembles Class III and IV lupus nephritis in humans. These findings sparked a major collaboration with human geneticists in many Universities in America and Europe, who analysed five single-nucleotide polymorphisms found in TNIP1 (the gene encoding ABIN1) in samples from European-American, African American, Asian, Gullah, and Hispanic participants in a Large Lupus Association Study. This identified one polymorphism present in European Americans and another in African Americans that are strongly associated with the risk of developing kidney disease in Lupus. These findings suggest that drugs that suppress the MyD88-dependent signaling network may have potential for the treatment and/or prevention of lupus nephritis and that the ABIN1[D485N] knock-in mice may be a good model for pre-clinical testing of the efficacy of these compounds.
ABIN1 is a polyubiquitin-binding protein that plays an important role in restricting the strength of activation of the MyD88 signaling network in the innate immune system. In an paper published a couple of years ago Sambit Nanda found that knock-in mice in which Asp485 of ABIN1 was mutated to Asn, to generate a a polyubiquitin-binding-defective mutant, developed a lupus-like autoimmune disease. He found that the disease was caused by the hyper-activation of the MyD88-dependent signaling network because it was prevented by crossing the ABIN1[D485N] mice to MyD88 knock-out mice (Nanda et al, 2011, J. Exp. Med. 208, 1215-1228). In the new paper, published on-line on August 22nd in the Journal of the American Society of Nephrology, the ABIN1[D485N] mice were found to develop progressive glomerular nephritis (GN), which closely resembles Class III and IV lupus nephritis in humans. These findings sparked a major collaboration with human geneticists in many Universities in America and Europe, who analysed five single-nucleotide polymorphisms found in TNIP1 (the gene encoding ABIN1) in samples from European-American, African American, Asian, Gullah, and Hispanic participants in a Large Lupus Association Study. This identified one polymorphism present in European Americans and another in African Americans that are strongly associated with the risk of developing kidney disease in Lupus. These findings suggest that drugs that suppress the MyD88-dependent signaling network may have potential for the treatment and/or prevention of lupus nephritis and that the ABIN1[D485N] knock-in mice may be a good model for pre-clinical testing of the efficacy of these compounds.