Eleni Z Giannopoulou1, Christiane Winkler1,2, Ruth Chmiel1, Claudia Matzke1, Marlon Scholz1, Andreas Beyerlein1, Peter Achenbach1,2, Ezio Bonifacio3,4,5, Anette-G Ziegler6,7. 1. Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany. 2. Forschergruppe Diabetes e.V., Neuherberg, Germany. 3. Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität, Dresden, Germany. 4. Paul Langerhans Institute of the Helmholtz Zentrum München at University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 5. Institute of Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany. 6. 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. 7. Forschergruppe Diabetes e.V., Neuherberg, Germany. anette-g.ziegler@helmholtz-muenchen.de.
Abstract
AIMS/HYPOTHESIS: 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/ INTERPRETATION: Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.
AIMS/HYPOTHESIS: 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/ INTERPRETATION:Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.
Entities:
Keywords:
Incidence; Islet autoantibodies; Type 1 diabetes
Authors: Jeffrey P Krischer; Kristian F Lynch; Desmond A Schatz; Jorma Ilonen; Åke Lernmark; William A Hagopian; Marian J Rewers; Jin-Xiong She; Olli G Simell; Jorma Toppari; Anette-G Ziegler; Beena Akolkar; Ezio Bonifacio Journal: Diabetologia Date: 2015-02-10 Impact factor: 10.122
Authors: V Parikka; K Näntö-Salonen; M Saarinen; T Simell; J Ilonen; H Hyöty; R Veijola; M Knip; O Simell Journal: Diabetologia Date: 2012-03-23 Impact factor: 10.122
Authors: M Schenker; M Hummel; K Ferber; M Walter; E Keller; E D Albert; H U Janka; C Kastendiek; M Sorger; F Louwen; A G Ziegler Journal: Diabetologia Date: 1999-06 Impact factor: 10.122
Authors: W L Awa; B O Boehm; T Kapellen; B Rami; P Rupprath; W Marg; M Becker; R W Holl Journal: Eur J Endocrinol Date: 2010-04-06 Impact factor: 6.664
Authors: M Walter; E Albert; M Conrad; E Keller; M Hummel; K Ferber; B J Barratt; J A Todd; A-G Ziegler; E Bonifacio Journal: Diabetologia Date: 2003-05-16 Impact factor: 10.122
Authors: Anette G Ziegler; Marian Rewers; Olli Simell; Tuula Simell; Johanna Lempainen; Andrea Steck; Christiane Winkler; Jorma Ilonen; Riitta Veijola; Mikael Knip; Ezio Bonifacio; George S Eisenbarth Journal: JAMA Date: 2013-06-19 Impact factor: 56.272
Authors: Alistair J K Williams; Vito Lampasona; Michael Schlosser; Patricia W Mueller; David L Pittman; William E Winter; Beena Akolkar; Rebecca Wyatt; Cristina Brigatti; Stephanie Krause; Peter Achenbach Journal: Diabetes Date: 2015-05-13 Impact factor: 9.461
Authors: Laura M Jacobsen; Laura Bocchino; Carmella Evans-Molina; Linda DiMeglio; Robin Goland; Darrell M Wilson; Mark A Atkinson; Tandy Aye; William E Russell; John M Wentworth; David Boulware; Susan Geyer; Jay M Sosenko Journal: Diabetologia Date: 2019-11-25 Impact factor: 10.122
Authors: Christine von Toerne; Michael Laimighofer; Peter Achenbach; Andreas Beyerlein; Tonia de Las Heras Gala; Jan Krumsiek; Fabian J Theis; Anette G Ziegler; Stefanie M Hauck Journal: Diabetologia Date: 2016-11-04 Impact factor: 10.122
Authors: Brigitte I Frohnert; Lisa Ide; Fran Dong; Anna E Barón; Andrea K Steck; Jill M Norris; Marian J Rewers Journal: Diabetologia Date: 2017-03-17 Impact factor: 10.122
Authors: C S Hampe; J R Radtke; A Wester; A Carlsson; E Cedervall; B Jönsson; S A Ivarsson; H Elding Larsson; K Larsson; B Lindberg; J Neiderud; O Rolandsson; Å Lernmark Journal: Diabet Med Date: 2018-12-28 Impact factor: 4.359
Authors: Andrea K Steck; Alexandra Fouts; Dongmei Miao; Zhiyuan Zhao; Fran Dong; Jay Sosenko; Peter Gottlieb; Marian J Rewers; Liping Yu Journal: Diabetes Technol Ther Date: 2016-03-18 Impact factor: 6.118
Authors: Carla J Greenbaum; Cate Speake; Jeffrey Krischer; Jane Buckner; Peter A Gottlieb; Desmond A Schatz; Kevan C Herold; Mark A Atkinson Journal: Diabetes Date: 2018-05-16 Impact factor: 9.461