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Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen\u20102 (IA\u20102A), 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\u2010risk 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\u2010appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first\u2010appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3\u20134 years of age. GADA first appeared by 2\u20133 years of age to reach a plateau by about 4 years. Prior to the first\u2010appearing 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.<\/jats:p>","DOI":"10.1111\/joim.13648","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T01:25:49Z","timestamp":1683249949000},"page":"145-158","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Possible heterogeneity of initial pancreatic islet beta\u2010cell autoimmunity heralding type 1 diabetes"],"prefix":"10.1111","volume":"294","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1735-0499","authenticated-orcid":false,"given":"\u00c5ke","family":"Lernmark","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences Lund University CRC Sk\u00e5ne University Hospital  Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beena","family":"Akolkar","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hagopian","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Krischer","sequence":"additional","affiliation":[{"name":"Health Informatics Institute, Morsani College of Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"McIndoe","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Genomic Medicine, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Rewers","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Diabetes University of Colorado  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorma","family":"Toppari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Turku University Hospital, and Institute of Biomedicine, Research Centre for Integrated Physiology and Pharmacology University of Turku  Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra","family":"Vehik","sequence":"additional","affiliation":[{"name":"Health Informatics Institute, Morsani College of Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anette\u2010G.","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, and Klinikum rechts der Isar Technische Universit\u00e4t M\u00fcnchen, and Forschergruppe Diabetes e.V.  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