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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 747-754

Anti-Proteinase 3 Antibody Activation of Neutrophils Can Be Inhibited by alpha 1-Antitrypsin

Cyril P. Rooney, Clifford Taggart, Raymond Coakley, Noel G. McElvaney, and Shane J. O'Neill

Division of Respiratory Research, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin, Republic of Ireland

Wegener's granulomatosis (WG) is classically associated with the presence of cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA). Proteinase 3 (PR3), the target antigen for c-ANCA, is inhibited by the antiprotease alpha 1-antitrypsin (A1AT), and recent studies have demonstrated that WG patients who are A1AT-deficient have a worse clinical course, suggesting that a protease-antiprotease imbalance may play a role in WG. We evaluated the effect of A1AT on anti-PR3 antibody-induced activation of neutrophils. The neutrophil was chosen because of its central role in the pathogenesis of WG. Isolated neutrophils from healthy controls were incubated with tumor necrosis factor (TNF)-alpha to induce surface expression of PR3. Subsequently, they were stimulated with a monoclonal antibody to PR3, resulting in a significant increase in respiratory burst. Addition of A1AT (1 mg/ml) to the TNF-alpha - primed cells before the addition of the anti-PR3 antibody resulted in a 47% reduction in anti-PR3 antibody-induced activation. A1AT mediated this inhibitory action by preventing anti-PR3 antibody binding to PR3 on the cell, thereby preventing the PR3-Fcgamma R11a cross-linkage required for cell activation. Further, anti-PR3 antibody-induced activation of neutrophils from WG patients can be reduced by 56% with A1AT. These data suggest that protease-antiprotease interactions may play a pivotal role in neutrophil activation in WG.

Abbreviations: alpha 1-antitrypsin, A1AT; bovine serum albumin, BSA; cytoplasmic antineutrophil cytoplasmic autoantibodies, c-ANCA; enzyme-linked immunosorbent assay, ELISA; fluorescein isothiocyanate, FITC; immunoglobulin, Ig; interleukin, IL; monoclonal antibody, mAb; mean channel fluorescence, MCF; neutrophil elastase, NE; phosphate-buffered saline, PBS; proteinase 3, PR3; standard error of the mean, SEM; secretory leukoprotease inhibitor, SLPI; tumor necrosis factor, TNF; Wegener's granulomatosis, WG.




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