von Gunten Stephan, Schaub Alexander, Vogel Monique, Stadler Beda M, Miescher Sylvia, Simon Hans-Uwe
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Blood. 2006 Dec 15;108(13):4255-9. doi: 10.1182/blood-2006-05-021568. Epub 2006 Aug 10.
Human intravenous immunoglobulin (IVIg) preparations are increasingly used for the treatment of autoimmune diseases. Earlier work demonstrated the presence of autoantibodies against Fas in IVIg, suggesting that IVIg might be able to induce caspase-dependent cell death in Fas-sensitive cells. In this study, we demonstrate that sialic acid-binding Ig-like lectin 9 (Siglec) represents a surface molecule on neutrophils that is activated by IVIg, resulting in caspase-dependent and caspase-independent forms of cell death. Neutrophil death was mediated by naturally occurring anti-Siglec-9 autoantibodies present in IVIg. Moreover, the efficacy of IVIg-mediated neutrophil killing was enhanced by the proinflammatory cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma), and this additional cell death required reactive oxygen species (ROSs) but not caspases. Anti- Siglec-9 autoantibody-depleted IVIg failed to induce this caspase-independent neutrophil death. These findings contribute to our understanding of how IVIg preparations exert their immunoregulatory effects under pathologic conditions and may provide a possible explanation for the neutropenia that is sometimes seen in association with IVIg therapy.
人静脉注射免疫球蛋白（IVIg）制剂越来越多地用于治疗自身免疫性疾病。早期研究表明IVIg中存在抗Fas自身抗体，提示IVIg可能能够诱导Fas敏感细胞发生半胱天冬酶依赖性细胞死亡。在本研究中，我们证明唾液酸结合免疫球蛋白样凝集素9（Siglec）是中性粒细胞上的一种表面分子，可被IVIg激活，导致半胱天冬酶依赖性和非依赖性细胞死亡形式。中性粒细胞死亡由IVIg中天然存在的抗Siglec-9自身抗体介导。此外，促炎细胞因子粒细胞/巨噬细胞集落刺激因子（GM-CSF）和干扰素-γ（IFN-γ）增强了IVIg介导的中性粒细胞杀伤作用，这种额外的细胞死亡需要活性氧（ROS）而不是半胱天冬酶。去除抗Siglec-9自身抗体的IVIg未能诱导这种非半胱天冬酶依赖性中性粒细胞死亡。这些发现有助于我们理解IVIg制剂在病理条件下如何发挥免疫调节作用，并可能为IVIg治疗时有时出现的中性粒细胞减少提供一种可能的解释。
