Pathogenetic Pathways of Aberrant O‐glycosylation of IgA1 in an Autoimmune Disease, IgA Nephropathy

Abstract

IgA nephropathy (IgAN), a frequent cause of end‐stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose‐deficient O‐glycans (Gd‐IgA1; autoantigen) and anti‐glycan autoantibodies deposit in the glomeruli and induce renal injury. Serum IgA1 has 3‐6 clustered core 1 O‐glycans, some of which may be deficient in galactose. Patients with IgAN usually have elevated serum levels of Gd‐IgA1. The mechanisms involved in production of Gd‐IgA1 are not fully understood.Using IgA1‐producing cell lines, we have analyzed the heterogeneity of IgA1 O‐glycosylation and the corresponding biosynthetic pathways. IgA1 secreted by cells from IgAN patients vs. healthy controls had more O‐glycans and more galactose‐deficient sites. These changes were associated with differential expression/activity of key glycosyltransferases, elevated for an initiating enzyme GalNAc‐transferase 14 and for GalNAc‐specific sialyltransferase (ST6GalNAc‐II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1‐associated chaperone Cosmc. These findings were confirmed by siRNA knock‐down.Expression of these enzymes can be affected by cytokines that further enhance the enzyme imbalance, resulting in increased Gd‐IgA1 production.In summary, Gd‐IgA1, the key autoantigen in IgAN, is produced by IgA1‐secreting cells due to dysregulation of multiple key enzymes. These findings thus provide insight into possible targets for future disease‐specific therapy.Supported by NIH grants DK078244, DK082753, GM098539 and by a gift from IGA Nephropathy Foundation of America.