Open AccessThe activation of the neutrophil respiratory burst by anti‐neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation
Author(s) -
Radford,
Janet M. Lord,
Savage
Publication year - 1999
Publication title -
clinical & experimental immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 135
eISSN - 1365-2249
pISSN - 0009-9104
DOI - 10.1046/j.1365-2249.1999.01043.x
Subject(s) - protein kinase c , autoantibody , tyrosine phosphorylation , tyrosine kinase , nadph oxidase , receptor tyrosine kinase , protein tyrosine phosphatase , kinase , tyrosine , superoxide , immunology , phosphorylation , biology , chemistry , signal transduction , biochemistry , antibody , reactive oxygen species , enzyme
The ability of antineutrophil cytoplasm autoantibodies (ANCA) from patients with systemic vasculitis to stimulate protein kinase C (PKC) and tyrosine kinases was examined in human neutrophils. Using the superoxide dismutase‐inhibitable reduction of ferricytochrome C, the kinetics of ANCA‐induced superoxide (O 2 − ) production were characterized and subsequently manipulated by specific inhibitors of PKC and tyrosine kinases. With this approach, ANCA IgG, but not normal IgG or ANCA F(ab′) 2 fragments caused a time and dose dependent release of O 2 − from TNF‐α primed neutrophils. The kinetics of ANCA‐induced O 2 − production showed an initial 10–15 min lag phase compared to the N ‐formyl‐ l ‐methionyl‐ l ‐leucyl‐ l ‐phenylalanine response, suggesting differences in the signalling pathways recruited by these two stimuli. Inhibitor studies revealed that ANCA‐activation involved members of both the Ca 2+ ‐dependent and ‐independent PKC isoforms and also tyrosine kinases. ANCA IgG resulted in the translocation of the β II isoform of PKC at a time corresponding to the end of the lag phase of O 2 − production, suggesting that PKC activity may be instrumental in processes regulating the activity of the NADPH oxidase in response to ANCA. Tyrosine phosphorylation of numerous proteins also peaked 10–15 min after stimulation with ANCA but not normal IgG. These data suggest that PKC and tyrosine kinases regulate O 2 − production from neutrophils stimulated with autoantibodies from patients with systemic vasculitis.