title: Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes.
abstract: OBJECTIVE
  Autoantibodies that precede type 1 diabetes frequently develop in early childhood and target distinct beta cell proteins. The aim of this study was to determine the heterogeneity of islet autoantibody development and fate.
  
  
  METHODS
  The ages of development of insulin autoantibodies (IAA) and GAD autoantibodies (GADA), followed by multiple islet autoantibodies and progression to diabetes were examined in 2,441 children participating in two German birth cohorts.
  
  
  RESULTS
  In 218 children who developed islet autoantibodies, the first islet autoantibody-positive sample was characterised by single IAA in 80 (37%), multiple islet autoantibodies in 68 (31%) and single GADA in 63 (29%) children. Of the children who were single antibody positive at seroconversion, 35 (44%) IAA-positive and 15 (24%) GADA-positive children developed multiple islet autoantibodies. Single persistent antibodies had heterogeneous affinities; GADA were also heterogeneous in their binding to N-terminally truncated GAD65 and in an ELISA. Progression to diabetes occurred in >50% of children within 10 years in all groups that developed multiple islet autoantibodies and in 44% of children with persistent single high-affinity IAA or persistent single GADA that were positive in both a radiobinding assay and ELISA. The earliest autoantibody development was seen in children with single IAA that progressed to multiple islet autoantibodies or in those with persistent high-affinity single IAA, with a sharp peak in incidence observed at age 9 months. The peak incidence occurred at age 2 years for children who underwent seroconversion directly to multiple islet autoantibodies and at 5 years for children who first seroconverted to GADA and subsequently developed other autoantibodies. Seroconversion to low-affinity IAA or persistent single GADA occurred at a low incidence after the age of 9 months.
  
  
  CONCLUSIONS
  Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Eleni Z
authors.initials: EZ
authors.lastname: Giannopoulou
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Winkler
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Chmiel
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Matzke
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Marlon
authors.initials: M
authors.lastname: Scholz
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyerlein
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Achenbach
authors.affiliation: Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität, Dresden, Germany.|Paul Langerhans Institute of the Helmholtz Zentrum München at University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|Institute of Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany. anette-g.ziegler@helmholtz-muenchen.de.|Forschergruppe Diabetes e.V., Neuherberg, Germany. anette-g.ziegler@helmholtz-muenchen.de.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D010641:Phenotype; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007328:Insulin; D005968:Glutamate Decarboxylase
keywords: Incidence; Islet autoantibodies; Type 1 diabetes