title: Fc gamma RIIIb allele-sensitive release of alpha-defensins: anti-neutrophil cytoplasmic antibody-induced release of chemotaxins.
abstract: Antineutrophil cytoplasmic Abs (ANCA) can activate neutrophils in an FcgammaR-dependent manner, but the link between this ANCA-induced effect and mononuclear cell activation with the characteristic granuloma formation of Wegener's granulomatosis is unclear. Human alpha-defensins, small cationic antimicrobial peptides, are found in neutrophils and have chemotactic activity for T cells, dendritic cells, and monocytes. In this study, we quantitated the release of alpha-defensins (human neutrophil peptides 1-3) from human neutrophils after targeted FcgammaR cross-linking (XL). Homotypic XL of FcgammaRIIa, FcgammaRIIIb, or heterotypic XL of both receptors resulted in significant release of alpha-defensins, an effect also induced by both human polyclonal and murine monoclonal cytoplasmic staining ANCA (anti-proteinase 3). This release of alpha-defensins, as well as of other granule constituents (ANCA targets anti-proteinase 3 and myeloperoxidase and elastase), was significantly greater in donors homozygous for the NA1 allele of FcgammaRIIIb than in donors homozygous for NA2. Interestingly, the ANCA-induced release was completely inhibited by the IgG Fc-binding peptide TG19320, which blocks the IgG-Fc region from binding to FcgammaR. Based on their chemotactic properties, alpha-defensins and their release by ANCA may contribute to modulation of the acquired immune response and to granuloma formation. The greater activity of the FcgammaRIIIB-NA1 genotype may also explain the greater severity of disease and its flare-ups in patients with this allele.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Sumiaki
authors.initials: S
authors.lastname: Tanaka
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Winn
authors.initials: W
authors.lastname: Chatham
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fassina
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D000483:Alleles; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000502:physiology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002630:Chemotactic Factors / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D058851:GPI-Linked Proteins; D014890:Granulomatosis with Polyangiitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006801:Humans; D053146:Myeloblastin; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D012697:Serine Endopeptidases / Q000276:immunology; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D015703:Antigens, CD; D002630:Chemotactic Factors; D003432:Cross-Linking Reagents; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; C406427:human neutrophil peptide 3; D009195:Peroxidase; D012697:Serine Endopeptidases; D010196:Pancreatic Elastase; D053146:Myeloblastin