Submitted May 4, 2006
Accepted July 27, 2006
Immunological and functional evidence for anti-Siglec-9
autoantibodies in intravenous immunoglobulin (IVIg)
preparations
Stephan von Gunten, Alexander Schaub, Monique Vogel, Beda M. Stadler, Sylvia Miescher, and Hans-Uwe Simon*
Departments of Pharmacology and Immunology, University of Bern, Bern, Switzerland
Departments of Pharmacology & Immunology, University of Bern, and ZLB Behring AG, Bern, Switzerland
* Corresponding author; email: hus{at}pki.unibe.ch.
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 immunoglobulin-like lectin (Siglec)-9 represents a surface molecule on neutrophils that is activated by IVIg, resulting in both caspase-dependent and caspase-independent forms of cell death in these cells. Neutrophil death was mediated by naturally occurring anti-Siglec-9 autoantibodies that are present in IVIg. Moreover, the efficacy of IVIg-mediated neutrophil killing was enhanced by the pro-inflammatory cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-
, and this additional cell death required reactive oxygen species (ROS) 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.
