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FcRIIIb Allele-Sensitive Release of -Defensins: Anti-Neutrophil Cytoplasmic Antibody-Induced Release of Chemotaxins ¹

Sumiaki Tanaka^2,*, Jeffrey C. Edberg^3,*,, Winn Chatham^*, Giorgio Fassina and Robert P. Kimberly^*,

^* Division of Clinical Immunology and Rheumatology, Department of Medicine and Department of Microbiology, University of Alabama, Birmingham, AL 35294; and XEPTAGEN SpA, Pozzuoli, Italy

Antineutrophil cytoplasmic Abs (ANCA) can activate neutrophils in an FcR-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 -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 -defensins (human neutrophil peptides 1–3) from human neutrophils after targeted FcR cross-linking (XL). Homotypic XL of FcRIIa, FcRIIIb, or heterotypic XL of both receptors resulted in significant release of -defensins, an effect also induced by both human polyclonal and murine monoclonal cytoplasmic staining ANCA (anti-proteinase 3). This release of -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 FcRIIIb 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 FcR. Based on their chemotactic properties, -defensins and their release by ANCA may contribute to modulation of the acquired immune response and to granuloma formation. The greater activity of the FcRIIIB-NA1 genotype may also explain the greater severity of disease and its flare-ups in patients with this allele.

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