Dynamics of the disease process leading to type 1 diabetes in children with HLA-conferred disease susceptibility

Type 1 diabetes (T1D) is an immune-mediated endocrine disorder driven by progressive destruction of pancreatic insulin-producing beta cells. A presymptomatic period of highly variable duration precedes the onset of clinical T1D, during which autoantibodies to multiple beta-cell antigens are detected in the circulation. Thus far, the factors decisive for individual disease risk and the timing of disease onset have remained obscure. This thesis aimed at improving the early prediction of T1D by characterizing the genetic, immunological, and demographic factors associated with the progression rate to T1D and by describing the islet autoantibody dynamics during the first 15 years in human leukocyte antigen (HLA) -predisposed children. Newborn infants participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study were screened for HLA genotypes predisposing to T1D from cord blood. Eligible infants were invited to clinical follow-up, including assessment of islet cell antibodies (ICA) and autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) as markers of islet autoimmunity. Multiple non-HLA single-nucleotide polymorphisms (SNPs) were analyzed for potential associations with the progression rate. In young children, IAA and ZnT8A emerged commonly as the first autoantibodies, but at preschool age, IA-2A- and especially GADA-initiated autoimmunity became common. Loss of IAA positivity indicated delayed progression from seroconversion to diagnosis compared with stable IAA positivity. Rapid progressors to T1D were characterized by positivity for multiple (≥2) autoantibodies, high autoantibody titers, especially ICA, IAA, and IA-2A at seroconversion, and the homozygous FUT2 secretor genotype and the high-risk HLA-DQB1*02/*03:02 genotype. Rapid progression occurred in both young (age 7 years). Depending on age, the immunological characteristics of rapid progressors were diverse. Slow progressors were distinguished from other progressors by immunological characteristics present at seroconversion, but no factors were explicitly predictive of slow progression. Season of birth differed between slow and other progressors. No differences emerged in the non-HLA SNP distributions between slow and other progressors. This study demonstrated that rapid progressors differ from slower progressors by factors present at seroconversion. The primary islet autoantibody is characteristic of age, suggesting that age and the stage of immunological maturation contribute substantially to the disease process. Triggers of aggressive islet autoimmunity may be heterogeneous. The labile state of islet autoantibodies affects the risk for T1D. The findings in this thesis improve the estimation of preclinical diabetes risk and the timing of disease onset, providing a clinically valuable framework for individualizing the efforts to delay or prevent T1D.