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In Vitro Neutrophil Activation by Antibodies to Proteinase 3 and Myeloperoxidase from Patients with Crescentic Glomerulonephritis

CASPER F. M. FRANSSEN^*,, MINKE G. HUITEMA, ANNEKE C. MULLER KOBOLD, WIA W. OOST-KORT, PIETER C. LIMBURG, ANTON TIEBOSCH, COEN A. STEGEMAN^*, CEES G. M. KALLENBERG and JAN W. COHEN TERVAERT^*,

^* Division of Nephrology, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands.
Division of Clinical Immunology, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands.
Department of Pathology, University Hospital Groningen, Groningen, The Netherlands.

Correspondence to Dr. Casper F. M. Franssen, Department of Internal Medicine, Division of Nephrology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Phone: 31 50 3612621; Fax: 31 50 3619310; E-mail: m.j.s.graler{at}int.azg.nl

Abstract. Previously, it was found that patients with necrotizing crescentic glomerulonephritis (NCGN) and anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against proteinase 3 (anti-PR3) had a faster deterioration of renal function and more active renal vasculitic lesions than patients with ANCA directed against myeloperoxidase (anti-MPO). Because ANCA-mediated neutrophil activation is thought to play an important role in the pathophysiology of this form of glomerulonephritis, this study was conducted to determine whether anti-PR3 are capable of inducing a more pronounced activation of neutrophils in vitro than anti-MPO. To test this hypothesis, the release of reactive oxygen radicals, as assessed by ferricytochrome c reduction and by dihydrorhodamine 123 oxidation, and the release of granule constituents from healthy donor neutrophils upon stimulation with IgG fractions were measured from 17 anti-PR3- and 14 anti-MPO-positive patients with active NCGN. Patients with anti-PR3 had a higher renal activity index (P < 0.05) compared with patients with anti-MPO. IgG fractions from anti-PR3-positive patients induced more oxygen radical release from tumor necrosis factor--primed neutrophils compared with IgG fractions from anti-MPO-positive patients, as assessed by ferricytochrome c reduction (P < 0.05) and dihydrorhodamine 123 oxidation (P < 0.01). In addition, IgG fractions from anti-PR3-positive patients generated more neutrophil degranulation of ß-glucuronidase (P < 0.01) than IgG fractions from anti-MPO-positive patients. In conclusion, IgG fractions from anti-PR3-positive patients with NCGN are more potent activators of the respiratory burst and degranulation in vitro than IgG fractions from anti-MPO-positive patients. These observations may be relevant in view of the clinical differences between anti-PR3- and anti-MPO-positive patients with NCGN.

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