The presence of islet autoantibodies remains a reliable biomarker to identify individuals at high risk of developing type 1 diabetes. As such, these autoantibodies play a pivotal role in understanding the prodrome of diabetes and selecting individuals for both prevention and intervention clinical trials. Over the last few decades, studies have sought to investigate autoantibody prevalence after diabetes onset to better understand ongoing islet autoimmunity; however, many findings are contradictory, and little is known about factors that may influence autoantibody persistence. Generally, glutamate decarboxylase autoantibodies (GADAs) are the most prevalent autoantibodies after diagnosis, particularly in adults, whilst zinc transporter 8 autoantibodies (ZnT8A) prevalence declines more rapidly. However, when studies with islet autoantibody data at diagnosis are considered, it becomes clear that overall islet antigen‐2 autoantibodies (IA‐2A) tend to persist for longer than GADA or ZnT8A. In this review, we assess the major studies that have contributed to our understanding of autoantibody persistence after diabetes onset and what factors affect this. Islet autoantibodies may provide biomarkers for long‐term β‐cell function and insights into how to prevent ongoing islet autoimmunity but larger studies collecting samples at and decades after diabetes onset are required to leverage the information they could provide.
The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n=577] providing a diagnosis sample [range -1.0-2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8% and 40.1%, respectively, remained positive at final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (p<0.0001), longer diabetes duration (p<0.0001), and age-at-onset under 8 years (p<0.01-0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (p=0.005), and SNPs associated with autoimmunity RELA/11q13 (p=0.017), LPP/3q28 (p=0.004), and negatively with IFIH1/2q24 (p=0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (p=0.019) and weakly negatively with RELA/11q13 (p=0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.
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