Cytokines Alter IgA1 O-Glycosylation by Dysregulating C1GalT1 and ST6GalNAc-II Enzymes |
| |
Authors: | Hitoshi Suzuki Milan Raska Koshi Yamada Zina Moldoveanu Bruce A. Julian Robert J. Wyatt Yasuhiko Tomino Ali G. Gharavi Jan Novak |
| |
Affiliation: | From the ‡University of Alabama at Birmingham, Birmingham, Alabama 35294.;§Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.;¶Palacky University Olomouc, Olomouc 779 00, Czech Republic.;‖University of Tennessee Health Science Center, Memphis, Tennessee 38103, and ;**Columbia University, New York, New York 10032 |
| |
Abstract: | IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1). These immunodeposits originate from circulating immune complexes consisting of anti-glycan antibodies bound to Gd-IgA1. As clinical disease onset and activity of IgAN often coincide with mucosal infections and dysregulation of cytokines, we hypothesized that cytokines may affect IgA1 O-glycosylation. We used IgA1-secreting cells derived from the circulation of IgAN patients and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines. Of the eight cytokines tested, only IL-6 and, to a lesser degree, IL-4 significantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN patients. These cytokines reduced galactosylation of the O-glycan substrate directly via decreased expression of the galactosyltransferase C1GalT1 and, indirectly, via increased expression of the sialyltransferase ST6GalNAc-II, which prevents galactosylation by C1GalT1. These findings were confirmed by siRNA knockdown of the corresponding genes and by in vitro enzyme reactions. In summary, IL-6 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransferases. These data provide a mechanism explaining increased immune-complex formation and disease exacerbation during mucosal infections in IgAN patients. |
| |
Keywords: | Glycosylation Immunology Kidney Mucosal Immunology Nephrology IgA Nephropathy IgA1 O-Glycans |
|
|