Heat-aggregated IgA prepared from patients with IgA nephropathy increases priming of human neutrophils to produce inositol triphosphate following FMet-Leu-Phe stimulation in vitro

Abstract

It is envisaged that circulating IgA complexes play a primary role in the glomerular injury of IgA nephropathy, the most common glomerulonephritis worldwide. In this study, we examined the pathophysiological effects of IgA and IgG isolated from IgA-nephritic patients on the signal transduction of human neutrophils. Heat-aggregated forms and monomers of IgA and IgG were prepared from sera of 11 IgA-nephritic patients and 11 healthy controls. Signal transduction was studied by measuring the inositol triphosphate (IP3) production in neutrophils incubated with the immunoglobulin preparations. Different forms of IgA or IgG from IgA-nephritic patients failed to induce a significant increase in IP3 production directly as compared with control IgA or IgG. However, neutrophils preincubated with heat-aggregated IgA (HAA) from IgA-nephritic patients demonstrated a significant rise in IP3 production upon subsequent stimulation by a chemotactic peptide, FMet-Leu-Phe (FMLP); a similar finding was not observed with heat-aggregated IgG. HAA pretreatment of neutrophils increased FMLP-induced IP3 production in a dose-dependent manner. The raised IP3 production was not due to increased FMLP receptors, as HAA preincubation of neutrophils did not increase the binding of tritiated FMLP. The increased IP3 production upon FMLP stimulation in HAA-primed neutrophils was completely abolished by pertussis toxin in a dose-dependent manner. These findings tend to refute a direct stimulatory effect of HAA on phospholipase C, but, instead, may suggest that HAA prepared from IgA-nephritic patients upregulates the activation of G proteins in the plasma membrane. Our data suggest that HAA prepared from IgA-nephritic patients exert an upregulatory effect on signal transduction in neutrophils. These findings indirectly support the view that neutrophils are activated in IgA nephropathy and that they may play a contributory role in the inflammatory process of glomerular and interstitial injury.