Islet Autoantibody Testing: An End to the Trials and Tribulations?

Abstract

Islet autoantibodies have taught us almost all we know about the disease process leading up to type 1 diabetes (T1D). In the absence of direct access to target organ tissue prior to diagnosis, they have provided the best available window on islet autoimmunity in humans. Detection of islet cell antibodies (ICA) in unaffected relatives identified for the first time the prodrome preceding clinical onset (1), and autoantibodies to insulin (IAA), glutamate decarboxylase (GADA), islet antigen-2, and zinc transporter 8 now provide the foundations for studies of the natural history of the condition. In prospective studies from birth, such as Diabetes Autoimmunity Study of the Young (DAISY), BABYDIAB, Diabetes Prediction and Prevention (DIPP), and more recently The Environmental Determinants of Diabetes in the Young (TEDDY), appearance of islet autoantibodies has been used to define the onset of autoimmunity (2–5). This can then be related to genetic characteristics and environmental exposures of potential etiological relevance. Autoantibodies also form the basis of disease prediction, allowing the sensitive, specific, and quantified assessment of risk that has made possible intervention studies to delay or prevent clinical onset of T1D (6). Islet autoantibodies are, however, difficult to measure. Islet cell antibodies have been largely abandoned because the indirect immunofluorescence assays are complex, labor-intensive, and hard to standardize. Even for antibodies directed against the four identified islet autoantigens—and in spite of international workshop programs—assay performance varies markedly between laboratories and a relatively small number achieve high levels of sensitivity and specificity (7,8) Current assays pick up both disease-relevant and nondisease-associated (disease-irrelevant) signals. …