期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 8, 页码 5330-5339出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.512277
关键词
Glycosylation; Immunology; Kidney; Mucosal Immunology; Nephrology; IgA Nephropathy; IgA1; O-Glycans
资金
- National Institutes of Health [DK082753, DK078244, DK083663, GM098539]
- IGA Nephropathy Foundation of America
- European Social Fund [CZ.1.07/2.3.00/20.0164]
- Ministry of School, Youth, and Sport [LH11046]
- Czech Science Foundation [GAP302/10/1055]
- Grant Agency of the Ministry of Health, Czech Republic [NT11081]
- Grants-in-Aid for Scientific Research [24591213] Funding Source: KAKEN
Background: IgA1-producing cells of IgA nephropathy patients secrete IgA1 with galactose-deficient O-glycans; these IgA1 molecules form nephritogenic immune complexes. Results: Cytokines IL-6 and IL-4 accentuate IgA1 galactose deficiency via modulation of key glycosyltransferases. Conclusion: Some cytokines alter IgA1 O-glycosylation and increase production of nephritogenic IgA1 glycoforms. Significance: These data provide a mechanism explaining increased immune-complex formation in IgA nephropathy patients. 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.
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