Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases.
OBJECTIVE
Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate.


METHODS
Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats.


RESULTS
Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients.


CONCLUSIONS
These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.
Manto
Mario-Ubaldo
MU
Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium.
Laute
Marie-Aline
MA
Aguera
Michèle
M
Rogemond
Véronique
V
Pandolfo
Massimo
M
Honnorat
Jérome
J
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002846:Chromatography, Affinity; D004333:Drug Administration Routes; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects / Q000276:immunology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000294:innervation; D016202:N-Methylaspartate / Q000494:pharmacology; D009422:Nervous System Diseases / Q000097:blood / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology
D001323:Autoantibodies; D018690:Excitatory Amino Acid Agonists; D007074:Immunoglobulin G; D009569:Nitric Oxide; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005968:Glutamate Decarboxylase