Abstract
In IgA nephropathy (IgAN), pathogenic IgA1 is likely derived from bone marrow (BM) cells and exhibits reduced O-galactosylation. Defective O-galactosylation may arise from the compromised expression or function of the enzyme beta-galactosyltransferase and/or its molecular chaperone (Cosmc). We measured B-cell O-galactosylation activity and the relative gene expression of beta-galactosyltransferase and Cosmc in peripheral blood and BM taken from patients with IgAN and controls. O-galactosylation activity was measured in peripheral and BM B cells by the incorporation of radiolabeled galactose into an asialo-mucin acceptor. Gene expression of beta-galactosyltransferase and Cosmc was measured by real-time PCR and related to that of the enzyme GalNAc-T2 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-2), which synthesizes the core O-glycan. Neither the B-cell O-galactosylation activity nor the gene expression of the enzyme or chaperone was different between patients and controls. However, the relationships between the O-glycosylation of serum IgA1, galactosylation activity, and beta-galactosyltransferase gene expression showed different patterns in IgAN and controls. In IgAN, O-galactosylation activity correlated with beta-galactosyltransferase gene expression, but not with IgA1 O-glycosylation, suggesting that factors other than the availability of beta-galactosyltransferase or Cosmc are responsible for altered IgA1 O-glycosylation.
Highlights
IgA nephropathy (IgAN) is characterized by the deposition of IgA in the glomerular mesangium, and is among the most common forms of glomerulonephritis in developed countries.[1]
Initial linking of GalNAc to the protein backbone is catalyzed by one of the UDP-N-acetyl-a-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase family, known as GalNAc-T2.3 Galactosylation is effected by a core-1 b1-3 galactosyltransferase, C1Gal-T1.4 C1Gal-T1 activity requires the co-expression of the chaperone protein Core-1-b3-Gal-Tspecific molecular chaperone (Cosmc),[5] the availability of which may be a limiting factor in galactosyltransferase function
The lower percentage of B cells in bone marrow (BM) is probably due to the earlier expression of CD19 than CD22 by B cell precursors: CD22-negative cells had the morphological appearance of immature lymphocytes
Summary
IgA nephropathy (IgAN) is characterized by the deposition of IgA in the glomerular mesangium, and is among the most common forms of glomerulonephritis in developed countries.[1]. The IgA1 O-glycans are of the Core-1 type, short and simple sugar chains based on N-acetyl galactosamine (GalNAc) O-linked to serine or threonine residues. This can occur alone, but is usually extended with the addition of galactose (Gal) and sialic acid (N-acetylneuraminic acid, NeuNAc), giving rise to different O-glycan chain variants (I–V, Figure 1a). We measured BM C1Gal-T1 and Cosmc mRNA expression in relation to that of GalNAc-T2
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