TY - JOUR
T1 - Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes
AU - TEDDY Study Group
AU - Lernmark, Åke
AU - Akolkar, Beena
AU - Hagopian, William
AU - Krischer, Jeffrey
AU - McIndoe, Richard
AU - Rewers, Marian
AU - Toppari, Jorma
AU - Vehik, Kendra
AU - Ziegler, Anette-G
AU - Hyöty, Heikki
AU - Oikarinen, Sami
AU - Lönnrot, Maria
AU - Koreasalo, Mirva
AU - Kurppa, Kalle
AU - Hakola, Leena
AU - Ahonen, Suvi
AU - Åkerlund, Mari
AU - Mattila, Markus
AU - Virtanen, Suvi
AU - Lindfors, Katri
N1 - © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
PY - 2023/8
Y1 - 2023/8
N2 - The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.
AB - The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.
KW - Child
KW - Infant, Newborn
KW - Humans
KW - Diabetes Mellitus, Type 1/genetics
KW - Autoimmunity
KW - Autoantibodies
KW - Insulin
KW - Islets of Langerhans
KW - Observational Studies as Topic
KW - Multicenter Studies as Topic
U2 - 10.1111/joim.13648
DO - 10.1111/joim.13648
M3 - Article
C2 - 37143363
SN - 0954-6820
VL - 294
SP - 145
EP - 158
JO - Journal of Internal Medicine
JF - Journal of Internal Medicine
IS - 2
ER -