The pathogenesis of IgA nephropathy : the role of IgA molecule and the nature of IgA receptors
Abstract of thesis entitled
The pathogenesis of IgA nephropathy: the role of IgA molecule and
the nature of IgA receptors
Leung Chi Kam Joseph
for the degree of Doctor of Philosophy
at The University of Hong Kong
in March 2003
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide but the pathogenesis of this disease remains unclear. In the present study, the role of IgA molecule and their receptors in the pathogenesis of IgAN was examined.
IgA1 with different molecular weight isolated from serum of patients with IgAN were separated by FPLC. Lectin binding assays were used to study the sialylation and galactosylation profile of the ?- or ?-IgA1. Oversialylation of the high molecular weight (HMW) ?-IgA1 from IgAN patients was found. IgA were further separated into different charges by ion exchange chromatography and their binding to human mesangial cells (HMC) were examined. The anionic charged HMW IgA1 from patient was elevated and these anionic IgA bound more to HMC. Pre-incubation with poly-L-lysine increased the binding of HMW IgA1 to HMC and the binding was decreased following pre-incubation with heparin. These results suggest the important role of anionic charge in IgA1 deposition onto the HMC.
IgA receptors on leucocytes, hepatocytes and HMC plays a decisive role for the fate of IgA. The absence of IgA Fc receptor (FcaR1), asialoglycoprotein receptor (ASGPR) and polymeric immunoglobulin receptor (pIgR) on the surface of HMC was confirmed. The findings suggest that the predominant binding of IgA to HMC is mediated by other receptors or novel mechanisms. The binding characteristics of different molecular weight of serum IgA from IgAN patients to target cells including a liver cell line (HepG2), monocytic cell line (U937) and HMC were also studied. Different and distinct binding patterns were observed. HMC bound more HMW IgA whereas HepG2 and U937 mainly bound monomeric and intermediate size IgA. These characteristic binding properties could alter the catabolism of circulating IgA and, hence, predispose their deposition in the kidney mesangium in IgAN.
The circulating IgA level is determined by the rate of its production, the uptake by leukocytes, and the removal by hepatocytes. Increased binding of endogenous IgA to circulating granulocytes and monocytes in IgAN was demonstrated. FcaR1 expression on leukocytes was increased, independent of plasma IgA levels. Leucocytes from IgAN patients exhibited a higher binding capacity to exogenous IgA with a predominance of HMW IgA. Inhibition studies of binding suggest additional binding mechanism other than FcaR1 in the HMW IgA uptake by leukocytes.
The functional role of HMW IgA was examined by investigating the HMW IgA-induced MIF synthesis in HMC. HMW IgA increased MIF and
TNF-a gene and protein expression. MIF production in HMC induced by HMW IgA was abolished by neutralizing antibody to TNF-a suggesting that upregulation of MIF synthesis in HMC is mediated via an amplifying proinflammatory loop involving TNF-a.
In summary, the present study shows that the size, charge and carbohydrate composition of HMW IgA1 in patients IgAN play important roles in the pathogenesis of IgAN. The interaction between these aberrant HMW IgA1 with the targets cells will ultimately determine the selective mesangial deposition of HMW IgA1. The findings will serve as theoretical basis for developing new diagnostic and therapeutic approaches for this important and common kidney disorder.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:iga glomerulonephritis kidney glomerulus diseases
Date of Publication:01/01/2003