Novel diabetes autoantibodies and prediction of type 1 diabetes

Abstract

Autoantibodies are currently the most robust biomarkers of type 1 diabetes and are frequently used to establish entry criteria for the participation of genetically at-risk individuals in secondary prevention/intervention clinical trials. Since their original description almost 40 years ago, considerable efforts have been devoted toward identifying the precise molecular targets that are recognized. Such information can have significant benefit for developing improved metrics for identifying/stratifying of at-risk subjects, developing potential therapeutic targets, and advancing understanding of the pathophysiology of the disease. Currently, four major molecular targets ([pro]insulin, GAD65, IA-2, and ZnT8) have been confirmed, with approximately 94% of all subjects with a clinical diagnosis of type 1 diabetes expressing autoantibodies to at least one of these molecules at clinical onset. In this review, we summarize some of the salient properties of these targets that might contribute to their autoantigenicity and methods that have been used in attempts to identify new components of the humoral autoresponse.

Fig. 1

Combining ZnT8A with IAA, GADA, and IA2A assays increases the sensitivity of autoimmune detection. Sera obtained from recently diabetic subjects ranging in age from 2 to 40 years were assayed in parallel with RIAs to insulin (INS), GAD65 (GAD), IA-2, and ZnT8. Overall prevalence is shown for each antigen, although it should be noted that this can vary significantly with age of onset, especially for IAA. In this cohort, the combined measurement of GADA, IAA, and IA2A detected autoimmunity in ∼86% of subjects. Inclusion of ZnT8A increased this to ∼96%, and ∼25% reduction in the number of autoantibody negative individuals

Fig. 2

Homo-dimeric ZnT8 antigen probes enhance sensitivity. Sera from newly diabetic subjects were assayed in parallel with monomeric and homo-dimeric ZnT8 variant probes. Detected prevalences with monomers versus dimers were X v Y, X1 v Y1, and X2 v Y2 for the R, W, and Q probe pairs, respectively. Red lines indicate cutoff values