Underplycosylated IgA1 Associated With Renal Pathology And Clinical In Patients With IgA Nephropathy

Objective: IgA nephropathy (IgAN) is a mesangial proliferative glomerulonephritis in which IgAl predominantly deposits in glomerular mesangium. Human IgAl has a series of inucin-type O-glycans linked to serine or threonine residues in the hinge region between the CHI and CH2 domains of the a 1 heavy chain. The O-glycans can maintain the three-dimensional shape and normal physical functions of IgAl molecule. Each O-glycan is based on a core N-acetyl galaclosaimine (GalNac) O-linked to the amino acid backbone. The majority of the moieties are further extended with 1,3-linked D-galactose(Gal) to form the Gal P l,3GalNAc disaccharide and with one or two sialic units in a 2,3 linkage with Gal or a 2,6 linkage with GalNAc. Although normal serum IgAl consists of a mixture of O-glycoforms due to the microheterogeneity of carbo-hydrates, the IgAl molecule in IgAN has increased terminal GalNAc that was called underglycosylation. The under-glycosylated IgAl deposits in mesangium through many ways. The underglycosylated IgAl aggregated to be macro-molecule IgAl. The underglycosylated IgAl induces the generation ofautoantibody of GalNAc or hinge region peptide. The underglycosylated IgAl adheres to mesangial cell by binding with Fc a receptor expressed by mesangial cell and/or by mannose-bind lectin(MBL) way. The under-glycosylated IgAl can also bind strongly to matrix proteins in mesangium, including Type IV collagen, fibronectin and laminin. The present study was undertaken to elucidate the relationship between underglycosylated IgAl and renal pathology and clinical in IgAN, and to understand the pathogenetic role of underglycosylated IgAl in IgAN.Methods: Sixty-eight renal biopsy cases with IgAN, 20 with nephrotic minimal disease were included. The vicia villosa lectin(VVL) can bind the GalNAc units of IgAl molecule. The VVL binding capacity of the serum IgAl samples was measured in ELISA-type systems to reflect the level of IgAl glycosylation(The increased binding capacity means IgAl molecule's underglycosylation). The deposition of the under-glycosylated IgAl was detected by fluorescein conjugated VVL under fluorscent photomicroscope. The correlation of serum IgAl glycosylation level, the grader of the immuno-fluorescence(IF) of underglycosylated IgAl in mesangium and clinical features was studied in IgAN.Results: The VVL binding capacity to strum IgAl in IgAN was significantly higher than control (4.56 + 3.08AU/mg VS. 2.83+1.02AU/mg p?.05). The creatinine clearance rate showed significantly lower in serum IgAlunderglycosyla-tion group(n=20) than the normal glycosylation group(n=48) in IgAN(77.02?6.30ml/min vs. 96.17+18.77ml/min p<0.05). But the level of serum IgAl glycosylalion showed no correlation with the other clinical characteristics (gender, blood pressure, hematuria, proteinuria, albumin, serum creatinine, BUN, osmoliliry) and the grade of IF (p>0.05). The grade of IF was higher in renal function insufficiency group in IgAN than the normal group(p<0.05), lower in the nephrotic syndrome group than the chronic glomerulo-nephritis group(p<0.05).Conclusion: The serum IgAl and the deposited IgAl in glomerular mesangium were all indicated to be underglycosylated in IgAN. High glycosylation level and IF grade were not correlated with renal pathology, but they could reflect the insufficient renal function. Segmental necrotizing lesions of the capillary wall, not the glycosylation level or IF grade, significantly affect hematuria in IgA nephropathy; Low glycosylation level and IF grade were correlated with heavy proteinuria and decreased serum albumin concentration in IgAN.