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IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1
Hitoshi Suzuki, … , Jiri Mestecky, Jan Novak
Hitoshi Suzuki, … , Jiri Mestecky, Jan Novak
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):629-639. https://doi.org/10.1172/JCI33189.
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Research Article Nephrology

IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1

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Abstract

Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by β1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine–specific α2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in β1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine–specific α2,6-sialyltransferase activity. Also, expression of β1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine–specific α2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target.

Authors

Hitoshi Suzuki, Zina Moldoveanu, Stacy Hall, Rhubell Brown, Huong L. Vu, Lea Novak, Bruce A. Julian, Milan Tomana, Robert J. Wyatt, Jeffrey C. Edberg, Graciela S. Alarcón, Robert P. Kimberly, Yasuhiko Tomino, Jiri Mestecky, Jan Novak

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Figure 3

Analysis of IgA1 fractionated by size-exclusion chromatography.

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Analysis of IgA1 fractionated by size-exclusion chromatography.
Culture ...
Culture supernatants from the 3 randomly selected IgAN-IgA1S cell lines (filled circles) and 2 HC-IgA1S cell lines (open circles) were separated by size-exclusion chromatography. Concentration of IgA1 in the fractions was determined by ELISA (A). Western blotting analysis after SDS-PAGE separation under nonreducing conditions confirmed distinct molecular forms of IgA in various fractions (inset in A). (B) Gal deficiency of IgA1 was determined by HAA-ELISA. Trimeric and dimeric IgA1 secreted by IgAN-IgA1S cell lines had high reactivity with HAA, while monomeric IgA1 did not react. Furthermore, IgA1 secreted by HC-IgA1S cell lines was mostly monomeric and did not react with HAA. Data are expressed as mean ± SD.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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