Glycosylation of circulating IgA in patients with IgA nephropathy modulates proliferation and apoptosis of mesangial cells

• Published in: Journal of the American Society of Nephrology Vol. 12; no. 9; pp. 1862 - 1871
• Main Authors: AMORE, Alessandro, CIRINA, Paola, CONTI, Giovanni, BRUSA, Paola, PERUZZI, Licia, COPPO, Rosanna
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-09-2001
• Subjects: Apoptosis - physiology; Biological and medical sciences; Cell Division - physiology; Cells, Cultured; Galactose - metabolism; Glomerular Mesangium - pathology; Glomerular Mesangium - physiopathology; Glomerulonephritis; Glomerulonephritis, IGA - metabolism; Glomerulonephritis, IGA - pathology; Glycoproteins - blood; Glycosylation; Humans; Immunoglobulin A - blood; Immunoglobulin A - metabolism; Immunoglobulin A - physiology; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Reference Values; Sialic Acids - metabolism; Kidney disease; Human; Glomerulonephritis; Immunopathology; IgA; Urinary system disease; Mesangial cell; Cell death; Circulating current; Glycosylation; In vitro; Apoptosis
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.V1291862

Abnormalities in circulating IgA1 have been demonstrated in patients with IgA nephropathy (IgAN). This study addresses the question of the functional significance of this alteration in creating mesangial injury. Biologic effects of selected IgA glycoforms isolated from serum of IgAN patients and controls and in vitro deglycosylated normal IgA were tested on cultured human mesangial cells (MC). IgA glycoforms, ranging from 250 to 500 kD molecular weight, were isolated by lectin affinity chromatography followed by HPLC. IgA and IgG content was measured by enzyme-linked immunosorbent assay. HPLC fractions were incubated with MC to evaluate proliferation and apoptosis rates and nitric oxide synthesis. Moreover, MC were conditioned with in vitro desialylated and degalactosylated normal IgA. Patients with IgAN displayed increased levels of IgA glycoforms exposing sialic acid in alpha2,6 linkage with N-acetylgalactosamine (Neu5Acalpha2,6GalNAc) (P < 0.02) and GalNAc (P < 0.05), indicating truncation of O-linked glycans of IgA1. Moreover, IgA glycoforms with increased exposure of mannose were observed (P < 0.03), suggesting a defective N-linked glycosylation. No modification in IgG glycosylation was detected. When incubated with MC, the IgA glycoforms isolated from patients with increased exposure of GalNAc, Neu5Acalpha2,6GalNAc, or mannose, significantly depressed the proliferation and increased the apoptotic rate and nitric oxide synthesis activity of cultured MC, in comparison with fractions isolated from controls. Similarly, in vitro desialylated and degalactosylated IgAs significantly depressed the proliferation and enhanced the apoptosis rates of MC. In conclusion, a significant modulation of several human MC functions exerted by serum IgA with increased exposure of GalNAc, Neu5Acalpha2,6GalNAc, and mannose residues isolated from IgAN patients is reported for the first time.