Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibody-mediated injury in a model of acute motor axonal neuropathy.
Anti-GD1a ganglioside antibodies (Abs) are the serological hallmark of the acute motor axonal form of the post-infectious paralysis, Guillain-Barre syndrome. Development of a disease model in mice has been impeded by the weak immunogenicity of gangliosides and the apparent resistance of GD1a-containing neural membranes to anti-GD1a antibody-mediated injury. Here we used mice with altered ganglioside biosynthesis to generate such a model at motor nerve terminals. First, we bypassed immunological tolerance by immunizing GD1a-deficient, beta-1,4-N-acetylgalactosaminyl transferase knock-out mice with GD1a ganglioside-mimicking antigens from Campylobacter jejuni and generated high-titer anti-GD1a antisera and complement fixing monoclonal Abs (mAbs). Next, we exposed ex vivo nerve-muscle preparations from GD1a-overexpressing, GD3 synthase knock-out mice to the anti-GD1a mAbs in the presence of a source of complement and investigated morphological and electrophysiological damage. Dense antibody and complement deposits were observed only over presynaptic motor axons, accompanied by severe ultrastructural damage and electrophysiological blockade of motor nerve terminal function. Perisynaptic Schwann cells and postsynaptic membranes were unaffected. In contrast, normal mice were not only unresponsive to immunization with GD1a but also resistant to neural injury during anti-GD1a Ab exposure, demonstrating the central role of membrane antigen density in modulating both immune tolerance to GD1a and axonal susceptibility to anti-GD1a Abmediated injury. Identical paralyzing effects were observed when testing mouse and human anti-GD1a-positive sera. These data indicate that anti-GD1a Abs arise via molecular mimicry and are likely to be clinically relevant in injuring peripheral nerve axonal membranes containing sufficiently high levels of GD1a.
Goodfellow
John A
JA
Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, United Kingdom.
Bowes
Tyrone
T
Sheikh
Kazim
K
Odaka
Masaaki
M
Halstead
Susan K
SK
Humphreys
Peter D
PD
Wagner
Eric R
ER
Yuki
Nobuhiro
N
Furukawa
Koichi
K
Furukawa
Keiko
K
Plomp
Jaap J
JJ
Willison
Hugh J
HJ
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology*; D001369:Axons / Q000276:immunology; D016123:Campylobacter jejuni / Q000276:immunology; D003167:Complement Activation; D004195:Disease Models, Animal; D005732:Gangliosides / Q000096:biosynthesis / Q000276:immunology*; D020275:Guillain-Barre Syndrome / Q000209:etiology / Q000276:immunology; D007108:Immune Tolerance; D007114:Immunization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018716:Molecular Mimicry / Q000276:immunology*; D009046:Motor Neurons / Q000276:immunology / Q000502:physiology*; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000235:genetics; D020721:Nervous System Autoimmune Disease, Experimental / Q000209:etiology / Q000276:immunology*; D009469:Neuromuscular Junction / Q000276:immunology* / Q000503:physiopathology / Q000648:ultrastructure; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D000942:Antigens, Bacterial; D001323:Autoantibodies; D001324:Autoantigens; D005732:Gangliosides; D017350:N-Acetylgalactosaminyltransferases; D012799:Sialyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C021298:ganglioside, GD1a; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
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