Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 118, Issue 2, Pages 629-639Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI33189
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Funding
- NCRR NIH HHS [M01 RR00211, M01 RR000211, M01 RR000032, M01RR00032] Funding Source: Medline
- NIAMS NIH HHS [AR49084, P01 AR049084] Funding Source: Medline
- NIDDK NIH HHS [P01 DK061525, R01 DK047322, R24 DK064400, R01 DK071802, DK47322, DK61525, DK64400, DK78244, DK71802, R01 DK078244, R56 DK078244] Funding Source: Medline
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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 beta 1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine-specific alpha 2,6-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 beta 1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine-specific alpha 2,6-sialyltransferase activity. Also, expression of beta 1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine-specific a2,6-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.
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