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Brain Advance Access published online on February 25, 2004
Brain, doi:10.1093/brain/awh127
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© 2004 The Guarantors of Brain

Article

Anti-ganglioside antibody-mediated neuronal cytotoxicity and its protection by intravenous immunoglobulin: implications for immune neuropathies

G. Zhang 1, P. H. H. Lopez 2, C. Y. Li 3, N. R. Mehta 4, J. W. Griffin 2, R. L. Schnaar 4, and K. A. Sheikh 5*

1 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA; Department of Neurology, The Second Teaching Hospital, Hebei Medical University, Shijiazhuang, People’s Republic of China
2 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
3 Department of Neurology, The Second Teaching Hospital, Hebei Medical University, Shijiazhuang, People’s Republic of China
4 Department of Pharmacology, Johns Hopkins University, Baltimore, MD, USA
5 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA; Department of Neurology, Johns Hopkins Hospital, 600 N. Wolfe St, 509 Pathology Building, Baltimore, MD 21287, USA

* Corresponding author. E-mail: ksheik{at}jhmi.edu.

Received 8 October 2003 ; revised 18 December 2003 ; accepted 22 December 2003

Abstract

Antibodies against GD1a, GM1 and related gangliosides are frequently present in patients with the motor variant of Guillain-Barré syndrome (GBS), and their pathological role in this variant of GBS is now widely accepted. However, two basic issues related to anti-ganglioside antibody-mediated neural injury are not completely resolved: (i) some anti-ganglioside antibodies can cross-react with glycoproteins and therefore the nature of antigens targeted by these antibodies is not well established; and (ii) although pathological studies suggest that complement activation occurs in GBS, experimental data for the role of complement remain inconclusive. To address these issues, we developed and characterized a simple anti-ganglioside antibody-mediated cytotoxicity assay. Our results demonstrate first, that both GBS sera containing anti-ganglioside antibodies and monoclonal anti-ganglioside antibodies cause neuronal cell lysis by targeting specific cell surface gangliosides, and secondly, that this cell lysis is complement dependent. In this assay, the GD1a cell membrane pool appears to be more susceptible to anti-ganglioside antibody-mediated injury than the GM1 pool. Further, human intravenous immunoglobulin (IVIg), now a standard treatment for GBS, significantly decreased cytotoxicity in this assay. Our data indicate that the mechanisms of IVIg-mediated protection in this assay include anti-idiotypic antibodies and downregulation of complement activation. This simple cytotoxicity assay can potentially be used for screening of (i) pathogenic anti-ganglioside antibodies in patients with immune-mediated neuropathies; and (ii) new/experimental therapies to prevent anti-ganglioside antibody-mediated neural injury.

Keywords: cytotoxicity assay; Guillain-Barré syndrome; acute motor axonal neuropathy; anti-ganglioside antibodies; IVIg
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