Submitted December 29, 2005
Accepted December 15, 2006
Intravenous immunoglobulins contain naturally occurring antibodies that mimic anti-neutrophil cytoplasmic antibodies and activate neutrophils in a TNF-alpha dependent and Fc-receptor independent way
Sven Jarius, Peter Eichhorn, Michael H Albert, Stefan Wagenpfeil, Manfred Wick, Bernd H Belohradsky, Reinhard Hohlfeld, Dieter E Jenne, and Raymond Voltz*
Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany
Institute of Clinical Chemistry, Ludwig Maximilians University, Munich, Germany
Dr. v. Haunersches Kinderspital, Ludwig Maximilians University, Munich, Germany
Institute of Medical Statistics and Epidemiology, Technical University, Munich, Germany
Dept of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
Dept of Palliative Medicine, University of Cologne, Cologne, Germany
* Corresponding author; email: raymond.voltz{at}uk-koeln.de.
Intravenous immunoglobulin (IVIg) preparations are increasingly used for therapy of several neuroimmunological diseases. IVIg therapy is considered safe, although serious side effects like aseptic meningitis, cerebral vasospasm or ischemic encephalopathy have been reported. These side effects are frequently associated with neutrophilic pleocytosis in the cerebro-spinal fluid (CSF) suggesting a neutrophil mediated mechanism. To elucidate the potential role of neutrophil activation we analyzed IVIG preparations from five different commercial sources for the presence of ANCA-like immunoglobulins against ethanol-fixed peripheral blood neutrophils, purified human antigens and a panel of human and non-human tissues. All IVIg batches tested (n=13) contained atypical ANCA (IgG titer up to 1:2048, IgA up to 1:512). Moreover, all preparations were capable of inducing hydrogen peroxide production in TNF-alpha primed human neutrophils, with a significant correlation (p<0.005) between atypical ANCA titers in IVIg preparations and neutrophil activation. Fc-mediated binding and activation was ruled out by the use of IVIg-F(ab')2 fragments. Our findings strongly suggest that in vivo activation of TNF
-primed neutrophils by atypical ANCA of IVIg may contribute to the side effects of IVIg therapy, and for the first time demonstrate that the activation of neutrophil granulocytes by IVIg occurs in a Fc receptor (FcR)-independent, hence antigen-dependent way.
