title: Recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different GAD antibody-positive phenotypes.
abstract: Autoantibodies against the smaller isoform of glutamic acid decarboxylase (GAD) are markers for Type 1 diabetes. GAD65 autoantibody (GAD65Ab)-positive individuals in the general population are, however, mostly at low risk of developing Type 1 diabetes, suggesting that GAD65Ab phenotypes may be associated with different underlying pathogenic processes. The aim of this study was to test the hypothesis that Type 1 diabetes patients (n = 243; group I), GAD65Ab-positive healthy individuals (n = 28; group II), and healthy first-degree relatives of Type 1 diabetes patients (n = 41; group III) have antibody phenotypes that recognize different GAD65 epitopes. Sera from groups I-III were tested for their binding to GAD65 and GAD67, as well as six different GAD65/67 fusion proteins. Regardless of group, sera reactive to both GAD65 and GAD67 showed broader epitope reactivity than GAD65-specific sera. Furthermore, Type 1 diabetes patients showed a more restricted epitope binding than healthy individuals and first-degree relatives, demonstrating significantly less binding to the N-terminal part of GAD65 and to GAD67. Our analysis demonstrates that the N-terminal part is essential for full antibody binding to GAD65, in particular, to the middle epitope. It is suggested that Type 1 diabetes is associated with restricted GAD65Ab epitope specificity.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98195, USA. champe@u.washington.edu
authors.forename: C S
authors.initials: CS
authors.lastname: Hampe
authors.forename: L P
authors.initials: LP
authors.lastname: Hammerle
authors.forename: L
authors.initials: L
authors.lastname: Bekris
authors.forename: E
authors.initials: E
authors.lastname: Ortqvist
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.forename: O
authors.initials: O
authors.lastname: Rolandsson
authors.forename: M
authors.initials: M
authors.lastname: Landin-Olsson
authors.forename: C
authors.initials: C
authors.lastname: Törn
authors.forename: B
authors.initials: B
authors.lastname: Persson
authors.forename: A
authors.initials: A
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D010641:Phenotype; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007527:Isoenzymes; D011994:Recombinant Proteins; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2