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 three to six clustered O-glycans, some of which may be deficient in galactose and thus expose terminal or sialylated N-acetylgalactosamine. 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 galactose-deficient sites and overall more O-glycans. These changes were associated with differential expression/ activity of key glycosyltransferases in cells from patients with IgAN vs. controls, elevated for an initiating enzyme N-acetylgalactosaminyl (GalNAc)- transferase 14 and for GalNAc-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1- associated chaperone Cosmc. Involvement of the key enzymes in the production of Gd-IgA1 was confirmed by siRNA knockdown and biochemical approaches. Moreover, expression of these enzymes is affected by some cytokines that further enhance the enzyme imbalance to increase Gd-IgA1 production. In summary, the production of Gd-IgA1, the key autoantigen in IgAN, by IgA1- secreting cells results from dysregulation of key glycosyltransferases and is augmented by certain cytokines. These findings provide insight into possible approaches for future disease-specific therapy.
CITATION STYLE
Novak, J., Takahashi, K., Suzuki, H., Reily, C., Stewart, T., Ueda, H., … Renfrow, M. B. (2016). Heterogeneity of aberrant O-glycosylation of IgA1 in IgA nephropathy. In Pathogenesis and Treatment in IgA Nephropathy: An International Comparison (pp. 53–68). Springer Japan. https://doi.org/10.1007/978-4-431-55588-9_4
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