M. Li Vecchi

Evidence that the interaction between circulating IgA and fibronectin is a normal process enhanced in primary IgA nephropathy

A solid-phase ELISA was set up to measure the direct binding capacity (BC) of different, commercially available, purified human IgA preparations to plates coated with human fibronectin (FN). It was found that secretory, polymeric, and, to a much lesser extent, monomeric IgA exhibited elevated FN-BC as compared to their BC to plates coated with bovine serum albumin. This binding was specific since not observed with human IgG or IgM antibodies. In addition, we noted that this interaction was dose dependent, Ca2+ dependent, saturable, and not covalent, was inhibited by soluble FN, but not by a prior incubation of FN-coated plates with anti-human fibronectin antibodies, and appeared to involve on the dimeric FN other structures than its heparin-binding, collagen-binding, or C1q-binding domains. Similar experiments conducted with normal plasma indicated that plasma IgA, but not plasma IgG or IgM, was also capable of significant binding to FN-coated plates. In contrast, serum IgA did not significantly bind to those plates under otherwise identical experimental conditions. Thus, the coagulation process induces a strong decrease in the FN-BC of circulating IgA, which implies the necessity of using plasma rather than serum to study such interactions. The apparent molecular weight of plasma IgA interacting with FN-coated plates ranged between 450 and 900 kd, and its major binding characteristics were quite similar to those observed with purified polymeric IgA. The FN-BC of plasma IgA was then measured by the same ELISA in 30 patients with primary IgA nephropathy (IgAN) and in 23 healthy controls. The mean FN-BC of plasma IgA was significantly higher in patients than in normal controls. This enhancement was due mainly to the augmentation in the concentration of circulating “macromolecular” IgA and was significantly correlated with the plasma levels of IgA-FN complexes. However, the pathogenetic role of these findings was probably not determinant since similar observations were made in alcoholic liver cirrhosis without urinary abnormalities and since the FN-BC of plasma IgA or the plasma levels of IgA-FN complexes were not correlated with the various biological parameters of evolutivity of primary IgAN. In conclusion, these studies suggest that the ability of polymeric IgA to directly bind to FN is involved in the formation of circulating IgA-FN complexes and that this normal binding process, although enhanced in IgAN, is probably not responsible for kidney injury, at least in the patients studied.

No pathogenic role of enhanced plasma IgA binding capacity to fibronectin and IgA-fibronectin aggregates in Henoch-Schönlein purpura.

Dr. J.-C. Davin, Het Emma Kinderziekenhuis, AMC, 9, Meibergdreef, NL-1005 AZ Amsterdam Z-O (The Netherlands) Dear Sir, Numerous clinical and histological observations suggest that the pathogenesis of HenochSchönlein purpura (HSP) nephritis is related to the deposition of circulating complexes containing IgA in the glomerular mesangium [1]. Several authors [2-4] have demonstrated the presence of circulating aggregates containing IgA and fibronectin (FN) in HSP nephritis and IgA nephropathy (IgAN) as well. Some authors [2, 3] postulate that these aggregates bind to glomerular collagen and induce renal lesions, while our previous work [4] strongly suggests that IgA-FN complexes do not play any pathogenic role in IgAN and result from an enhancement of IgA physiological binding to FN, related to increased polymeric IgA plasma concentrations [4]. As HSP in children is often observed without any renal symptoms [5], this illness represents an ideal clinical model for clarifying the pathogenic role of circulating IgAFN complexes and of the FN-binding capacity of IgA. We have, therefore, measured by previously described enzyme-linked immuno-sorbent assay methods [4] the amount of circulating IgA-FN aggregates and the FN-binding capacity of plasma IgA in 15 children (10 males and 5 females, 3-18 years of age) presenting with HSP. Five of them presented with no renal signs (no urinary abnormalities, no reduced creatinine clearance) at the time of testing, whereas the remaining 10 displayed hematuria, associated with pro-teinuria in 2 of them. Besides typical cutaneous and gastrointestinal signs, the diagnosis of HSP was also ascertained by the demonstration of either significant IgA glomerular mesangial deposits (5 cases) or a leukocy-toclastic vasculitis with granular dermal IgA deposits (10 cases). The control group consisted of 15 age-matched children undergoing blood examination for the purpose of surgical procedures (orchidopexy, hernia, phimosis, etc.). The FN-binding capacity (optical density; mean ± SD) of plasma IgA measured in patients with HSP was significantly (p < 0.05) higher (0.70 ± 0.40) than that observed in controls (0.43 ± 23). However, an increased FN-binding capacity of plasma IgA was not more frequently found in patients with renal symptoms (4 of 10) than in the others (3 of 5). The