Cellular Signaling and Production of Galactose-Deficient IgAl in IgA Nephropathy, an Autoimmune Disease

摘要

Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgAl-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgAl (galactose-deficient in some O-glycans; Gd-IgAl) with formation of nephritogenic Gd-IgAl-containing immune complexes. Gd-IgAl is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgAl in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgAl by IgAl-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgAl-producing cells is related to the production of Gd-IgAl. As Gd-IgAl is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgAl-producing cells will provide insight into possible targets for future disease-specific therapy.