Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan.
Biochem Biophys Res Commun. 2012 Jan 13;417(2):794-9. doi: 10.1016/j.bbrc.2011.12.038. Epub 2011 Dec 16.
Intravenous immunoglobulin (IVIG) is currently a very important therapeutic used for not only infectious diseases, but also for autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). Untoward reactions of IVIG have been thought to result from complement activation by aggregated IgG in IVIG. In addition, the aggregates have been known to activate neutrophils, which may result in the untoward reactions. However, the effect and mechanism of IVIG on neutrophils remain unclear. In this study, we investigated the activation of neutrophils by IVIG in terms of their reactive oxygen species (ROS) emission to elucidate the mechanisms. IVIG-induced ROS emission from purified neutrophils was remarkably augmented by TNF-α priming of the cells. The ROS emission from TNF-α-primed neutrophils occurred by activation with whole gammaglobulin (GG) molecules, but not F(ab')(2), Fc, or a mixture of F(ab')(2) and Fc. ROS emission by GG was inhibited by the F(ab')(2) fragment and an inhibitory antibody against FcγRIII. These results suggest that binding of IVIG to not only surface antigen(s), but also FcγRIII on neutrophils, is involved in IVIG-induced ROS emission from TNF-α-primed neutrophils, and contribute to the untoward reactions of IVIG.
静脉注射免疫球蛋白（IVIG）目前是一种非常重要的治疗方法，不仅用于传染病，也用于自身免疫性疾病，如特发性血小板减少性紫癜（ITP）。人们认为 IVIG 的不良反应是由于 IVIG 中聚集的 IgG 激活补体所致。此外，已知聚集物可激活中性粒细胞，从而导致不良反应。然而，IVIG 对中性粒细胞的作用和机制仍不清楚。在这项研究中，我们研究了 IVIG 对中性粒细胞的激活作用，以阐明其活性氧（ROS）的释放机制。通过 TNF-α 预刺激细胞，IVIG 可显著增强纯化中性粒细胞的 ROS 释放。TNF-α 预刺激的中性粒细胞通过与全免疫球蛋白（GG）分子而不是 F(ab')(2)、Fc 或 F(ab')(2)和 Fc 的混合物发生 ROS 释放。ROS 的释放由 GG 被 F(ab')(2)片段和针对 FcγRIII 的抑制性抗体抑制。这些结果表明，IVIG 与中性粒细胞表面抗原（s）和 FcγRIII 的结合参与了 TNF-α 预刺激的中性粒细胞中 IVIG 诱导的 ROS 释放，并导致 IVIG 的不良反应。
