title: Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity.
abstract: Antibodies to glutamic acid decarboxylase (GAD-ab) associate to different neurological syndromes. It is unknown if the diversity in syndrome association represents epitopes in different immunodominant domains or co-existence of antibodies to other proteins of the inhibitory synapsis. We examined the serum and CSF of 106 patients with anti-GAD related syndromes (39 cerebellar ataxia, 32 stiff-person syndrome [SPS], 18 epilepsy, and 17 limbic encephalitis [LE]). GAD65-ab titres were quantified by ELISA. Immunoblot was used to determine if the antibody-targeted epitopes of GAD65 and GAD67 were linear. A cell-based assay (CBA) with HEK293 cells expressing the GAD65 N-terminal, central catalytic domain, or C-terminal was used to investigate the immunodominant domains. Antibodies to GAD67, gamma-aminobutyric acid A receptor (GABAaR), glycine receptor (GlyR), GABAaR-associated protein (GABARAP), and gephyrin were determined with CBA. GAD-ab internalization was investigated using cultured rat hippocampal neurons. CSF GAD65-ab titres were higher in patients with cerebellar ataxia and LE compared to those with SPS (p = 0.02). GAD67-ab were identified in 81% of sera and 100% of CSF. GAD65-ab recognized linear epitopes in 98% of the patients and GAD67-ab in 42% (p<0.001). The GAD65 catalytic domain was recognized by 93% of sera, and the three domains by 22% of sera and 74% of CSF (p<0.001). Six patients had GABAaR-ab and another 6 had GlyR-ab without association to distinctive symptoms. None of the patients had gephyrin- or GABARAP-ab. GAD65-ab were not internalized by live neurons. Overall, these findings show that regardless of the neurological syndrome, the CSF immune response against GAD is more widespread than that of the serum and that there is no specific association between clinical phenotype and the presence of antibodies against other proteins of the inhibitory synapsis.
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Gresa-Arribas
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service of Neurology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Ariño
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service of Neurology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Martínez-Hernández
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Petit-Pedrol
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sabater
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service of Neurology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
authors.affiliation: Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service of Neurology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D015551:Autoimmunity; D002675:Child, Preschool; D000939:Epitopes / Q000276:immunology; D005260:Female; D059330:GABAergic Neurons / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000276:immunology*; D017966:Pyramidal Cells / Q000276:immunology; D051381:Rats; D013569:Synapses / Q000276:immunology; D013577:Syndrome; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2