title: Antimyeloperoxidase antibodies rapidly induce alpha-4-integrin-dependent glomerular neutrophil adhesion.
abstract: Patients with antineutrophil cytoplasmic antibodies (ANCAs) frequently develop severe vasculitis and glomerulonephritis. Although ANCAs, particularly antimyeloperoxidase (anti-MPO), have been shown to promote leukocyte adhesion in postcapillary venules, their ability to promote adhesion in the glomerular vasculature is less clear. We used intravital microscopy to examine glomerular leukocyte adhesion induced by anti-MPO. In mice pretreated with LPS, 50 microg anti-MPO induced LFA-1-dependent adhesion in glomeruli. In concert with this finding, in mice pretreated with LPS, more than 80% of circulating neutrophils bound anti-MPO within 5 minutes of intravenous administration. However, even in the absence of LPS, more than 40% of circulating neutrophils bound anti-MPO in vivo, a response not seen in MPO(-/-) mice. In addition, a higher dose of anti-MPO (200 microg) induced robust glomerular leukocyte adhesion in the absence of LPS. The latter response was beta2-integrin independent, instead requiring the alpha4-integrin, which was up-regulated on neutrophils in response to anti-MPO. These data indicate that anti-MPO antibodies bind to circulating neutrophils, and can induce glomerular leukocyte adhesion via multiple pathways. Lower doses induce adhesion only after an infection-related stimulus, whereas higher doses are capable of inducing responses in the absence of an additional inflammatory stimulus, via alternative adhesion mechanisms.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kuligowski
authors.forename: Rain Y Q
authors.initials: RY
authors.lastname: Kwan
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lo
authors.forename: Cyndi
authors.initials: C
authors.lastname: Wong
authors.forename: Will G
authors.initials: WG
authors.lastname: James
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bourges
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Latasha D
authors.initials: LD
authors.lastname: Abeynaike
authors.forename: Pam
authors.initials: P
authors.lastname: Hall
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000937:Antigen-Antibody Reactions; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology*; D019446:Endotoxemia / Q000276:immunology; D004731:Endotoxins / Q000494:pharmacology / Q000633:toxicity; D006869:Hydronephrosis / Q000276:immunology / Q000473:pathology; D007114:Immunization; D039441:Integrin alpha4 / Q000378:metabolism / Q000502:physiology*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D019007:P-Selectin / Q000276:immunology; D009195:Peroxidase / Q000172:deficiency / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D004731:Endotoxins; D016169:Lymphocyte Function-Associated Antigen-1; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; C044101:endotoxin, Escherichia coli; D009195:Peroxidase