Heat-Aggregated IgA Prepared from Patients with IgA Nephropathy Increases Calcium Mobilization and Superoxide Production of Human Neutrophils in vitro

Abstract

IgA nephropathy, characterized by predominant mesangial IgA deposition, is the commonest glomerulonephritis worldwide. It is envisaged that circulating IgA plays a primary role in the glomerular injury of IgA nephropathy. In this study, we examined the pathophysiologic effect of IgA and IgG isolated from IgA nephritic patients on the signal transduction and oxidative metabolism of human neutrophils. Heat-aggregated forms, monomers, and F(ab’)₂ fragments of IgA and IgG were prepared from sera of 11 IgA nephritic patients and 11 healthy controls. Signal transduction was studied by measuring calcium mobilization and oxidative metabolism by measuring superoxide production. Different forms of IgA and IgG from patients with IgA nephropathy did not induce a significant increase in calcium mobilization directly. Nonetheless, neutrophils preincubated with heat-aggregated IgA or IgG from IgA nephritic patients demonstrated a significant rise in calcium mobilization upon subsequent stimulation by a chemotactic peptide, FMet-Leu-Phe (FMLP). Heat-aggregated IgA or IgG pretreatment of neutrophils increased FMLP-induced calcium mobilization in a dose-dependent manner. Aggregated IgA or IgG prepared by heat aggregation from IgA nephritic patients induced a significantly greater superoxide production from neutrophils than immunoglobulins from healthy controls. Similarly, heat-aggregated IgA and IgG induced superoxide production in a dose-dependent manner. Our data suggest that heat-aggregated forms of IgA and IgG exert an upregulatory effect on signal transduction and oxidative metabolism in human neutrophils. These findings indirectly support the view that neutrophils could be activated in IgA nephropathy and may potentially be participating in the inflammatory process of glomerular and interstitial injury.