title: Immune reactivity to GAD25 in type 1 diabetes mellitus.
abstract: While both isoforms of glutamic acid decarboxylase (GAD) function as important autoantigens in autoimmune diabetes mellitus-GAD65 in humans and GAD67 in the NOD mouse-GAD67 is not synthesized in human pancreatic islets and is thought not to be an autoantigen in human diabetes. We have recently shown, however, that human islets contain a GAD67 splice variant: GAD25. Given the evidence that GAD67 could be a key diabetogenic autoantigen in the NOD mouse and the high prevalence of GAD65 autoantibodies in human type 1 diabetes, it became important to ask whether there is also immune reactivity to GAD25 in type 1 diabetes-possibly implicating it in the pathogenesis of the disease-and whether GAD25 reactivity could, like GAD65 reactivity, function as a clinically useful marker for the disease. We also hypothesized that the presence of autoantibodies to the smaller splice variant could be a cause of the up to 30% prevalence of GAD67 autoreactivity associated with type 1 diabetes. We therefore analyzed GAD25 reactivity in 105 newly-diagnosed children with type 1 diabetes and 74 control subjects. While 14 (13%) of the diabetic subjects were positive for GAD67 autoantibodies, only 3 (3%) were positive for GAD25 reactivity, none of which were GAD67 antibody-positive. Analysis of reactivity to a GAD67 chimera was consistent with GAD67 binding activity being due to cross-reactive GAD65 antibodies. Immunostaining confirmed the presence of GAD25 in human islets, revealing GAD25-positive cells to be sparse. Our results indicate that autoreactivity to GAD25 is rare in newly diagnosed type 1 diabetes and does not underlie GAD67 reactivity.
authors.affiliation: Robert H. Williams Laboratory, Department of Medicine, HSB K-161, Box 357710, University of Washington, Seattle, WA 98195-7710, USA. chessler@u.washington.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chessler
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Eva
authors.initials: E
authors.lastname: Ortqvist
authors.forename: William T
authors.initials: WT
authors.lastname: Simonson
authors.forename: Lynn
authors.initials: L
authors.lastname: Bekris
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D011869:Radioligand Assay
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1