Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations.
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.
von Gunten
Stephan
S
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Schaub
Alexander
A
Vogel
Monique
M
Stadler
Beda M
BM
Miescher
Sylvia
S
Simon
Hans-Uwe
HU
D015703:Antigens, CD / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001323:Autoantibodies / Q000009:adverse effects / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000819:agonists / Q000494:pharmacology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000009:adverse effects / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000819:agonists / Q000494:pharmacology; D037102:Lectins / Q000276:immunology*; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
D015703:Antigens, CD; D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous; D037102:Lectins; D017382:Reactive Oxygen Species; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor