title: Extrapancreatic autoantibody profiles in type I diabetes.
abstract: Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.
authors.affiliation: Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, and National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA. burbelop@nidcr.nih.gov
authors.forename: Peter D
authors.initials: PD
authors.lastname: Burbelo
authors.forename: Evan E
authors.initials: EE
authors.lastname: Lebovitz
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Bren
authors.forename: Ahmad
authors.initials: A
authors.lastname: Bayat
authors.forename: Scott
authors.initials: S
authors.lastname: Paviol
authors.forename: Janet M
authors.initials: JM
authors.lastname: Wenzlau
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Barriga
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
mesh_terms: D000251:Adenosine Triphosphatases / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D016022:Case-Control Studies; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007453:Iodide Peroxidase / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008156:Luciferases; D009414:Nerve Growth Factors / Q000276:immunology; D015221:Potassium Channels / Q000276:immunology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000276:immunology; D013270:Stomach / Q000276:immunology* / Q000473:pathology; D011503:Transglutaminases / Q000276:immunology
chemical_list: D001323:Autoantibodies; C473317:KCNRG protein, human; D009414:Nerve Growth Factors; D015221:Potassium Channels; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D007453:Iodide Peroxidase; D008156:Luciferases; D011503:Transglutaminases; D000251:Adenosine Triphosphatases