Fc gamma RIIIb allele-sensitive release of alpha-defensins: anti-neutrophil cytoplasmic antibody-induced release of chemotaxins.

Academic Article

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

    Published In

    Keywords

  • Alleles, Antibodies, Antineutrophil Cytoplasmic, Antigens, CD, Chemotactic Factors, Cross-Linking Reagents, Cytoplasmic Granules, GPI-Linked Proteins, Granulomatosis with Polyangiitis, Humans, Myeloblastin, Neutrophils, Pancreatic Elastase, Peroxidase, Receptors, IgG, Serine Endopeptidases, alpha-Defensins

    • Digital Object Identifier (doi)

    Author List

  • Tanaka S; Edberg JC; Chatham W; Fassina G; Kimberly RP

    • Start Page

  • 6090

    • End Page

  • 6096

    • Volume

  • 171

    • Issue

  • 11