No abstract

In the present study the involvement of the complement system (C) in the clearance of soluble IgA aggregates in the rat was studied. Monoclonal monomeric IgA (mIgA) antibody (which does not activate C) or aggregated polymeric IgA (aIgA; which activates C) were administered intravenously to phosphate-buffered saline-treated and complement-depleted [Cobra venom factor (CVF)-treated] rats and assessed for clearance from the circulation. In control rats, mIgA was cleared in a biphasic fashion with a first half-life (T1/2) of 29.5 +/- 14.2 min and a second T1/2 of 230 +/- 176 min. No differences were observed in clearance of mIgA in CVF-treated rats as compared to PBS-treated rats. In PBS-treated rats, aIgA with a size between 20 S and 150 S disappeared very rapidly from the circulation with a first T1/2 of 1.1 +/- 0.4 min and a second T1/2 of 23.2 +/- 11.3 min. In CVF-treated rats the clearance of aIgA was significantly delayed as compared to that in control rats, namely with a first T1/2 of 7.3 +/- 2.6 min and a second T1/2 of 64.2 +/- 19.4 min. Immunohistochemical studies of the liver (which is the main site of clearance of aIgA) revealed that Kupffer cells (KC) are mainly responsible for the uptake of aIgA. Furthermore, in PBS-treated rats aIgA deposition was accompanied by C3 deposition in the KC. In CVF-treated rats, the percentage of KC containing aIgA was significantly lower during the first 16 min after aIgA administration as compared to PBS treated rats. In addition no detectable C3 was found in KC of CVF-treated rats. These results indicate that KC play an important role in the clearance of large molecular weight IgA in rats and that C facilitates the clearance of these complexes from the circulation.

No abstract

IgA nephropathy is a clinically and histologically defined syndrome of unknown aetiology, which may have various causes in different parts of the world. Immunologically it is characterized by deposition of IgA1, probably polymeric IgA, in the mesangium and is frequently associated with IgG, C3 and components of the alternative pathway of the complement cascade. The disease can go into complete remission in children, but in adults it usually has a progressive course, characterized by the appearance of proteinuria and hypertension and loss of glomerular filtration rate (GFR). Histologically the development of glomerulosclerosis and tubulo-interstitial changes correlate with a clinical progressive course. The mucosal immune system is characterized by high plasma IgA 1 antibody responses after parenteral immunization with viral or bacterial vaccines. However, following nasal challenge with a bacterial neoantigen, IgA nephropathy patients appear to have a defective mucosal immune response in their nasal washes, in their bone marrow and in their plasma IgAl antibody levels.

Although a genetic predisposition to IgA nephropathy can be documented in a minority of patients, the majority ofcases are sporadic. The frequent association with mucosal infections suggest the aetiologic involvement of microbial antigens. However, no particular bacterial or viral strain has clearly been implicated. The involvement of mesangial or endothelial autoantigens has been suggested but not proven in a majority of cases. Most patients have a significantly higher memory repertoire of IgA forming B-lymphocytes in their bone marrow associated with high plasma levels of IgAl while the mucosally stimulated IgA response against recall antigens is augmented, the mucosal and plasma IgA response after mucosal stimulation by neoantigen is significantly reduced or absent. These observations suggest that IgA nephropathy patients have a defect in raising a mucosal IgA response against novel microbial antigens and that they will suffer from recurrent mucosal infections until they have developed a large enough repertoire of memory Bcells to protect their mucosal surfaces. AS a consequence of the recurrent stimulation of the IgA immune system, high levels of plasma IgA are found. The mechanism of IgA deposit formation in the mesangium is unknown. The ensuing inflammatory reaction in the glomeruli may vary from mild to severe, but usually the disease has an indolent course. The progression of IgA nephropathy to renal failure is clinically the most important complication. Recent observations on the role of cytokines in the pathogenesis of interstitial infiltration, interstitial fibrosis and tubular atrophy have created the opportunity to study and manipulate the process of renal scarring and the progression to renal failure.