A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia.
In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA(B) receptor (GABA(B)R). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA(B)R1 and rat GABA(B)R2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA(B)R1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA(B)R antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA(B)R that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.
Frisullo
Giovanni
G
Department of Neuroscience, Institute of Neurology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy.
Della Marca
Giacomo
G
Mirabella
Massimiliano
M
Caggiula
Marcella
M
Broccolini
Aldobrando
A
Rubino
Marco
M
Mennuni
Gioacchino
G
Tonali
Pietro Attilio
PA
Batocchi
Anna Paola
AP
D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003389:Cranial Nerve Diseases / Q000097:blood / Q000150:complications; D004195:Disease Models, Animal; D004569:Electroencephalography; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007074:Immunoglobulin G / Q000009:adverse effects; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009444:Neuritis, Autoimmune, Experimental / Q000209:etiology*; D051381:Rats; D018080:Receptors, GABA-B / Q000276:immunology*; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood / Q000209:etiology / Q000276:immunology*; D013997:Time Factors
D001323:Autoantibodies; D007074:Immunoglobulin G; D007527:Isoenzymes; D018080:Receptors, GABA-B; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2