Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations
Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations
复制标题
DOI：
10.1182/blood-2006-05-021568
复制
发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Simon, Hans-Uwe
中科院分区：
文献类型：
--
作者：
von Gunten, Stephan;Schaub, Alexander;Simon, Hans-Uwe
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。早期的工作证明了IVIg中存在抗Fas的自身抗体，这表明IVIg可能能够诱导Fas敏感细胞中的半胱天冬酶依赖性细胞死亡。在这项研究中，我们证明了唾液酸结合Ig样凝集素9（Siglec）代表中性粒细胞上的表面分子，其被IVIg激活，导致半胱天冬酶依赖性和半胱天冬酶非依赖性形式的细胞死亡。神经元死亡由IVIg中存在的天然存在的抗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的功效，并且这种额外的细胞死亡需要活性氧（Ross）而不是半胱天冬酶。抗Siglec-9自身抗体耗尽的IVIg未能诱导这种半胱天冬酶非依赖性中性粒细胞死亡。这些研究结果有助于我们了解免疫球蛋白制剂如何发挥其免疫调节作用的病理条件下，并可能提供一个可能的解释中性粒细胞减少症，有时看到与免疫球蛋白治疗。
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.