Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis.
OBJECTIVE
Microscopic polyangiitis (MPA) is a small-vessel vasculitis associated with antimyeloperoxidase (MPO) antibodies in 70% of patients. Anti-MPO antibodies can trigger the release of MPO by neutrophils and monocytes, but their involvement in the pathogenesis of MPA is still questioned. The aim of this study was to investigate whether anti-MPO antibodies can activate MPO to generate an oxidative stress that is potentially deleterious to the endothelium.


METHODS
MPA sera, purified IgG from MPA sera, normal control sera, and purified IgG from normal sera were incubated with MPO coated onto microtitration plates. The peroxidase activity of MPO was evaluated by adding o-phenylenediamine. Production of hypochlorous acid (HOCl) was determined by chemiluminescence. The cytotoxic properties of byproducts of MPO activation were tested on endothelial cells in culture.


RESULTS
MPA sera with anti-MPO antibodies were found to activate MPO in vitro (P < 0.0001 versus normal sera) and to generate HOCl (P < 0.001), as did IgG purified from MPA sera (P < 0.05). MPA sera without anti-MPO antibodies and MPA IgG absorbed on MPO did not show these activities. The byproducts of MPO activation by MPA sera exerted a strong cytolytic activity on endothelial cells in culture (P < 0.01). Both HOCl production and endothelial lysis were abrogated by N-acetylcysteine (NAC), an antioxidant molecule (P < 0.05 and P < 0.0001, respectively).


CONCLUSIONS
Anti-MPO antibodies could play a pathogenic role in vivo by triggering an oxidative burst, leading to severe endothelial damage. Treatment of MPA patients with NAC might be proposed in an attempt to abrogate these deleterious phenomena.
Guilpain
Philippe
P
Université Paris Descartes, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
Servettaz
Amélie
A
Goulvestre
Claire
C
Barrieu
Sandrine
S
Borderie
Didier
D
Chéreau
Christiane
C
Kavian
Niloufar
N
Pagnoux
Christian
C
Guillevin
Loïc
L
Weill
Bernard
B
Mouthon
Luc
L
Batteux
Frédéric
F
D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000097:blood / Q000276:immunology*; D012016:Reference Values; D014657:Vasculitis / Q000097:blood / Q000201:enzymology / Q000276:immunology*
D019268:Antibodies, Antineutrophil Cytoplasmic; D009195:Peroxidase