FcγRIIIb allele-sensitive release of α-defensins:: Anti-neutrophil cytoplasmic antibody-induced release of chemotaxins
FcγRIIIb allele-sensitive release of α-defensins:: Anti-neutrophil cytoplasmic antibody-induced release of chemotaxins
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DOI：
10.4049/jimmunol.171.11.6090
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Kimberly, RP
中科院分区：
文献类型：
--
作者：
Tanaka, SU;Edberg, JC;Kimberly, RP
抗中性粒细胞胞浆抗体(ANCA)可以以FcGammaR依赖的方式激活中性粒细胞，但这种ANCA诱导的效应与单个核细胞激活与韦格纳肉芽肿典型肉芽肿形成之间的联系尚不清楚。人α-防御素是一种小的阳离子抗菌肽，存在于中性粒细胞中，对T细胞、树突状细胞和单核细胞具有趋化活性。在这项研究中，我们定量了靶向FcGammaR交联(XL)后人中性粒细胞释放的α-防御素(人中性粒细胞多肽1-3)。FcGammaRIIa、FcGammaRIIIb的同型XL或两种受体的异型XL均可导致α-防御素的显著释放，这一效应也可由人多克隆和鼠单克隆胞浆染色ANCA(抗蛋白酶3)诱导。在FcGammaRIIIb的NA1等位基因纯合的捐赠者中，α-防御素以及其他颗粒成分(ANCA靶向抗蛋白酶3、髓过氧化物酶和弹力酶)的释放显著高于NA2纯合子的捐赠者。有趣的是，ANCA诱导的释放完全被Ig G Fc结合肽TG19320所抑制，TG19320阻断了Ig G-Fc区域与FcGammaR的结合。基于它们的趋化特性，α-防御素及其由ANCA释放可能有助于调节获得性免疫反应和肉芽肿的形成。FcGammaRIIIB-NA1基因的较大活性也可能解释了带有该等位基因的患者疾病更严重及其突发的原因。
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.