IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1.
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 beta1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine-specific alpha2,6-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 beta1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine-specific alpha2,6-sialyltransferase activity. Also, expression of beta1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine-specific alpha2,6-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.
Suzuki
Hitoshi
H
University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Moldoveanu
Zina
Z
Hall
Stacy
S
Brown
Rhubell
R
Vu
Huong L
HL
Novak
Lea
L
Julian
Bruce A
BA
Tomana
Milan
M
Wyatt
Robert J
RJ
Edberg
Jeffrey C
JC
Alarcón
Graciela S
GS
Kimberly
Robert P
RP
Tomino
Yasuhiko
Y
Mestecky
Jiri
J
Novak
Jan
J
D000328:Adult; D002461:Cell Line, Transformed; D005260:Female; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000276:immunology*; D005964:Glucosyltransferases; D006031:Glycosylation; D006056:Golgi Apparatus / Q000276:immunology; D004854:Herpesvirus 4, Human; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D012799:Sialyltransferases / Q000378:metabolism
D007070:Immunoglobulin A; C514116:B3GLCT protein, human; D005700:Galactosyltransferases; D005964:Glucosyltransferases; D012799:Sialyltransferases; C088391:galactosyl-1-3-N-acetylgalactosaminyl-specific 2,6-sialyltransferase; D019158:N-Acetylneuraminic Acid