Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy.
Anti-disialoside antibodies (Abs) that bind NeuAc(alpha2-8) 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 alpha-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.
Halstead
Susan K
SK
Division of Clinical Neurosciences, Institute of Neurological Sciences, University of Glasgow Southern General Hospital, Glasgow G51 4TF, UK.
O'Hanlon
Graham M
GM
Humphreys
Peter D
PD
Morrison
Deborah B
DB
Morgan
Bryan P
BP
Todd
Andrew J
AJ
Plomp
Jaap J
JJ
Willison
Hugh J
HJ
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D018957:CD59 Antigens / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D003167:Complement Activation / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D003165:Complement System Proteins / Q000032:analysis; D004996:Ethidium / Q000031:analogs & derivatives / Q000032:analysis; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007364:Intercalating Agents / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D016253:Microscopy, Immunoelectron / Q000379:methods; D009046:Motor Neurons / Q000276:immunology*; D009414:Nerve Growth Factors / Q000276:immunology*; D020721:Nervous System Autoimmune Disease, Experimental / Q000276:immunology*; D009469:Neuromuscular Junction / Q000276:immunology; D012583:Schwann Cells / Q000276:immunology*
D000906:Antibodies; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D005732:Gangliosides; D007364:Intercalating Agents; D009414:Nerve Growth Factors; C018533:ethidium homodimer; C039129:GQ1b ganglioside; D003165:Complement System Proteins; D004996:Ethidium