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Published online before print May 22, 2003

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(Journal of Leukocyte Biology. 2003;73:841-849.)
© 2003 by Society for Leukocyte Biology

Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO

Dominique Reumaux^*, Martin de Boer, Alexander B. Meijer, Patrick Duthilleul^* and Dirk Roos

^* Département d’Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France; and
Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands

Correspondence: Dr. Dominique Reumaux, Département d’Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, Avenue Désandrouin, 59322 Valenciennes Cedex, France. E-mail: reumaux-d{at}ch-valenciennes.fr

Anti-neutrophil cytoplasm autoantibodies (ANCA) directed against proteinase-3 and myeloperoxidase (MPO) activate tumor necrosis factor--primed neutrophils in vitro. We used neutrophils from one completely and one partially MPO-deficient donor to assess the requirement of MPO expression for neutrophil activation by anti-MPO antibodies. The MPO deficiencies were defined enzymatically, by immunocytochemistry and by immunoblotting. The mutations in the MPO genes of these donors were identified as a combination of a novel splice-site mutation at the 3' end of intron 11 (A-2C), a deletion of 14 nucleotides in exon 9 (A1555–C1568), and a novel C1907 T (636ThrMet) substitution in exon 11 in the completely MPO-deficient donor and as the same splice-site mutation and a novel C995 T (332AlaVal) substitution in exon 7 in the partially MPO-deficient donor. Monoclonal antibody 4.15 against MPO and MPO–ANCA–immunoglobulin G induced no superoxide anion production in these MPO-deficient neutrophils despite a normal production induced by other stimuli. Thus, the presence of MPO is a conditio sine qua non for neutrophil activation by anti-MPO antibodies. Moreover, we demonstrated that by means of these MPO-deficient cells, hydrogen peroxide may diffuse from neutrophils to surrounding cells, which may contribute to the damage induced by oxygen radicals in the pathology of systemic vasculitides.

Key Words: myeloperoxidase deficiency • MPO mutations • neutrophil activation • H₂O₂ carryover

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