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.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Lai
K N
KN
Department of Medicine, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin.
Leung
J C
JC
Li
P K
PK
D000595:Amino Acid Sequence; D005922:Glomerulonephritis, IGA / Q000097:blood* / Q000209:etiology; D006361:Heating; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000494:pharmacology* / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology*; D018375:Neutrophil Activation / Q000187:drug effects* / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D037342:Pertussis Toxin; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D015854:Up-Regulation / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007070:Immunoglobulin A; D010566:Virulence Factors, Bordetella; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015544:Inositol 1,4,5-Trisphosphate; D037342:Pertussis Toxin