Brain Advance Access originally published online on August 2, 2004
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Brain, Vol. 127, No. 9, 2109-2123,
September 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh231
Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy
1 Division of Clinical Neurosciences, Institute of Neurological Sciences, University of Glasgow Southern General Hospital, Glasgow G51 4TF, UK, Departments of 2 Neurophysiology and 3 Neurology, Leiden University Medical Centre, The Netherlands, 4 Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Cardiff CF14 4XN and 5 Spinal Cord Group, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow G12 8QQ, UK
Correspondence to: Professor Hugh J. Willison, University of Glasgow Department of Neurology, Ground Floor Neurology Block, Southern General Hospital, Glasgow G51 4TF, UK E-mail: h.j.willison{at}clinmed.gla.ac.uk
Anti-disialoside antibodies (Abs) that bind NeuAc(
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 distributed on 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 by abnormal 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.
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