Peripheral B lymphocyte β1,3‐galactosyltransferase and chaperone expression in immunoglobulin A nephropathy

Abstract

. Purpose. Aberrant O‐glycosylation of serum IgA1 is presumed to be one of the main pathogenesis of immunoglobulin A nephropathy (IgAN). β1,3‐galactosyltransferase (β1,3GT), whose activity requires coexistence of a specific chaperone, is the main enzyme which participate in the glycosylation process. The current study was carried out to elucidate the expression level of β1,3GT (C1GALT1) and its chaperone (Cosmc) in IgAN, and their relationships with clinical features as well as IgA glycosylation level. Design, setting and subjects. Forty‐one patients with IgAN, 21 patients with non‐IgAN glomerulonephritis and 26 normal controls were included in the present study. Peripheral B lymphocytes were isolated, and then expression level of C1GALT1 and Cosmc were quantitatively measured by real‐time reverse transcriptase polymerase chain reaction (RT‐PCR). Serum IgA level and glycosylation level were determined by enzyme‐linked immunosorbent assay (ELISA) and VV lectin‐binding method. Correlation analysis was performed between C1GALT1/Cosmc expression levels and clinical manifestations (severe proteinuria, renal dysfunction, gross haematuria). Results. B‐lymphocyte Cosmc gene expression level was significantly lower in IgAN patients than that of normal control and non‐IgAN patients (P < 0.05), whilst no apparent disparity was observed in C1GALT1 expression level. Cosmc expression showed a negative correlation with IgA O‐glycosylation level indicated by VV lectin‐binding assay. Statistical analysis also indicated that the level of Cosmc expression was negatively correlated with severe proteinuria (P < 0.05) instead of gross haematuria (P > 0.05). Conclusion. These data suggested that the aberrant IgA O‐glycosylation in IgAN was resulted from a downregulation of β1,3GT chaperone (Cosmc) expression in B lymphocyte, which is closely associated with clinical characteristics of the disease. This downregulation might be one of the fundamental pathogenic abnormalities in IgAN.

O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

“…In IgAN, IgA1 seems to be undergalactosylated, leading to increased exposure of terminal GalNAc. Defective expression or function of C1Gal-T has been suggested as a basis for this, and, more recently, underexpression of the chaperone protein Cosmc by peripheral blood cells has been demonstrated (25). However, altered IgA1 O-galactosylation cannot be attributed fully to a straightforward lack of galactosylating activity in affected individuals.…”

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

“…The stability and activity of this enzyme depends on a chaperone, Cosmc (25). Transcription of Cosmc has also been found to be reduced in IgAN patients (43). Mutations of this protein result in the production of Galdeficient O-linked glycans in Tn syndrome, a rare disease formerly called permanent mixed-field polyagglutinability, which is characterized by thrombocytopenia, leukopenia, and hemolytic anemia, but not nephritis (26, 44-46).…”

“…It has been suggested that B cells in the circulation of IgAN patients have lower expression and/or show less activity of β1,3-galactosyltransferase than such cells in healthy controls (42,43). The stability and activity of this enzyme depends on a chaperone, Cosmc (25).…”

Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity

“…The IgA1 in the circulation of patients with IgAN also carries Galdeficient O-glycans, although Gal-deficient variants are rarely found in the IgA1 in sera from normal individuals (7)(8)(9)15). The production of these variants is due to altered expression of specific glycosyltransferases in the IgA1-producing cells (16)(17)(18)(19).…”