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Published online before print May 22, 2003

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© 2003 by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1102567

Received for publication November 19, 2002.
Revised February 12, 2003.
Accepted for publication February 19, 2003.

Article

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

Dominique Reumaux ^*@, Martin de Boer , Alexander B. Meijerk , 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

^@ To whom correspondence should be addressed. E-mail: reumaux-d{at}ch-valenciennes.fr.

	Abstract

Antineutrophil 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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