Brain Advance Access published online on August 2, 2004
Brain, doi:10.1093/brain/awh231
© 2004 by Guarantors of Brain
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Division of Clinical Neurosciences, Institute of Neurological Sciences, University of Glasgow Southern General Hospital, Glasgow G51 4TF, UK; Spinal Cord Group, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow G12 8QQ, UK
* To whom correspondence should be addressed. E-mail: h.j.willison{at}clinmed.gla.ac.uk.
Summary Anti-disialoside antibodies (Abs) that bind NeuAc(
Revised May 6, 2004
Accepted May 9, 2004
Article
Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy
2 Division of Clinical Neurosciences, Institute of Neurological Sciences, University of Glasgow Southern General Hospital, Glasgow G51 4TF, UK
3 Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Cardiff CF14 4XN, UK
4 Spinal Cord Group, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow G12 8QQ, UK
5 Department of Neurophysiology, Leiden University Medical Centre, The Netherlands; Department of Neurology, Leiden University Medical Centre, The Netherlands
Abstract 
2-8) NeuAc epitopes on GQ1b and related gangliosides are found in human autoimmune neuropathy sera and are considered to be pathogenic. In a model system in mice, one mechanism by which anti-disialoside Abs have been demonstrated to induce paralysis is through a complement dependent blocking effect on transmitter release at the neuromuscular junction, similar to the effects of -latrotoxin. Although direct targeting of presynaptic neuronal membranes occurs in this model, concomitant injury to perisynaptic Schwann cells (pSC) could indirectly contribute to this paralytic effect by influencing nerve terminal function and survival. To examine this possibility and the specific complement components that might mediate these effects, we exposed neuromuscular junctions in vivo and in vitro to an anti-disialoside Ab in conjunction with intact and selectively deficient complement sources. Using immuno-electron microscopy, we observed Ab deposits equally distributedon both neuronal and pSC membranes, and ultrastructural evidence of injury at both sites. Presynaptic neuronal injury was demonstrated functionally with microelectrode recordings and histologically as neurofilament loss. As hypothesized, concomitant pSC injury occurred, as indicated byabnormal uptake of ethidium dimer into pSC nuclei. The pSC and nerve terminal damage indicators correlated well with deposition of the pore-forming terminal complement component, membrane attack complex (MAC) in pSC and nerve terminal membranes. Furthermore, both neuronal and pSC injury were exacerbated in tissues from mice lacking the inhibitory complement regulator, CD59, where MAC formation is increased. These data demonstrate that both presynaptic neuronal membranes and pSCs are targets for anti-disialoside Abs, and that the injury to both sites is mediated by MAC and further regulated by CD59. This is the first demonstration that complement mediated pSC injury occurs in a model of autoimmune neuropathy and provides a rationale for investigating the possibility of pSC injury in equivalent conditions in man.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. J. Plomp and H. J. Willison Pathophysiological actions of neuropathy-related anti-ganglioside antibodies at the neuromuscular junction J. Physiol., August 15, 2009; 587(16): 3979 - 3999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Lehmann, G. Meyer zu Horste, B. C. Kieseier, and H.-P. Hartung Review: Pathogenesis and treatment of immune-mediated neuropathies Therapeutic Advances in Neurological Disorders, July 1, 2009; 2(4): 261 - 281. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Kaida, T. Ariga, and R. K Yu Antiganglioside antibodies and their pathophysiological effects on Guillain-Barre syndrome and related disorders--A review Glycobiology, July 1, 2009; 19(7): 676 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Huizinga, R. Q. Hintzen, K. Assink, M. van Meurs, and S. Amor T-cell responses to neurofilament light protein are part of the normal immune repertoire Int. Immunol., April 1, 2009; 21(4): 433 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Lo MD Immunotherapy for anti-GQ1b IgG antibody-mediated disorders: role of electrophysiology in human trials Brain, April 1, 2009; 132(4): e104 - e104. [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Court, T. H. Gillingwater, S. Melrose, D. L. Sherman, K. N. Greenshields, A. J. Morton, J. B. Harris, H. J. Willison, and R. R. Ribchester Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions J. Cell Sci., December 1, 2008; 121(23): 3901 - 3911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Halstead, F. M. P. Zitman, P. D. Humphreys, K. Greenshields, J. J. Verschuuren, B. C. Jacobs, R. P. Rother, J. J. Plomp, and H. J. Willison Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model Brain, May 1, 2008; 131(5): 1197 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ramaglia, R. H. M. King, M. Nourallah, R. Wolterman, R. de Jonge, M. Ramkema, M. A. Vigar, S. van der Wetering, B. P. Morgan, D. Troost, et al. The Membrane Attack Complex of the Complement System Is Essential for Rapid Wallerian Degeneration J. Neurosci., July 18, 2007; 27(29): 7663 - 7672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Susuki, M. N. Rasband, K. Tohyama, K. Koibuchi, S. Okamoto, K. Funakoshi, K. Hirata, H. Baba, and N. Yuki Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers J. Neurosci., April 11, 2007; 27(15): 3956 - 3967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hoke Neuroprotection in the Peripheral Nervous System: Rationale for More Effective Therapies Arch Neurol, December 1, 2006; 63(12): 1681 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Geleijns, A. Roos, J. J. Houwing-Duistermaat, W. van Rijs, A. P. Tio-Gillen, J. D. Laman, P. A. van Doorn, and B. C. Jacobs Mannose-Binding Lectin Contributes to the Severity of Guillain-Barre Syndrome J. Immunol., September 15, 2006; 177(6): 4211 - 4217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Kaida, M Kanzaki, D Morita, K Kamakura, K Motoyoshi, M Hirakawa, and S Kusunoki Anti-ganglioside complex antibodies in Miller Fisher syndrome J. Neurol. Neurosurg. Psychiatry, September 1, 2006; 77(9): 1043 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Feng, S. Koirala, and C.-P. Ko Synapse-Glia Interactions at the Vertebrate Neuromuscular Junction Neuroscientist, October 1, 2005; 11(5): 503 - 513. [Abstract] [PDF]
|
|
|
|
|
|
J. A. Goodfellow, T. Bowes, K. Sheikh, M. Odaka, S. K. Halstead, P. D. Humphreys, E. R. Wagner, N. Yuki, K. Furukawa, K. Furukawa, et al. Overexpression of GD1a Ganglioside Sensitizes Motor Nerve Terminals to Anti-GD1a Antibody-Mediated Injury in a Model of Acute Motor Axonal Neuropathy J. Neurosci., February 16, 2005; 25(7): 1620 - 1628. [Abstract] [Full Text] [PDF]
|
|