Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.
The presence of anti-neutrophil cytoplasmic Abs (ANCA) in many patients with systemic vasculitis suggests that ANCA may play a role in disease pathogenesis. Neutrophils from patients with Wegener's granulomatosis often express ANCA target Ags (myeloperoxidase (MPO) and proteinase 3 (PR3)) on their surface, making these intracellular primary granule enzymes accessible to these autoantibodies. Similarly, normal neutrophils can be induced to translocate MPO and PR3 to the cell surface in vitro, and we demonstrate that murine mAb ANCA IgG, but not IgM, binds to the ANCA target and engages the Fc gamma RIIa ligand-binding site on the surface of human neutrophils. In contrast to ANCA IgM, ANCA IgG also induces an oxidative burst in neutrophils (oxidation of dihydrorhodamine = 91 +/- 15 fluorescence units with anti-PR3 IgG vs 17 +/- 2 with anti-PR3 IgM, p < 0.001). Blockade of the ligand-binding site of Fc gamma RIIa with an antibinding site mAb Fab significantly reduces this ANCA IgG-triggered production of reactive oxygen species (p < 0.01). Similarly, human ANCA bind the ANCA target, engage Fc gamma RIIa, and induce an oxidative burst in neutrophils. The allelic phenotype of Fc gamma RIIa strongly influences the Fc gamma receptor engagement by ligand, and Fc gamma RIIa homozygous donors differ by more than threefold in the quantitative production of reactive oxygen intermediates (ROI) (p < 0.01). Thus, engagement of Fc gamma RIIa by the Fc region of ANCA is one mechanism by which these autoantibodies activate receptor-mediated signal transduction systems in human neutrophils to initiate programs of inflammation and tissue injury. Fc gamma receptor alleles may represent heritable disease risk factors influencing the magnitude of such a process.
Porges
A J
AJ
Department of Medicine, Hospital for Special Surgery, Cornell University Medical College, New York, NY 10021.
Redecha
P B
PB
Kimberly
W T
WT
Csernok
E
E
Gross
W L
WL
Kimberly
R P
RP
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology; D014890:Granulomatosis with Polyangiitis / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D008024:Ligands; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D016897:Respiratory Burst; D014657:Vasculitis / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D017382:Reactive Oxygen Species; D017452:Receptors, IgG