T1D Autoantibodies: room for improvement?

Abstract

Purpose of review: Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin and other pancreatic β cells proteins including GAD65 (GADA), islet antigen 2 (IA-2A), and zinc transporter 8 (ZnT8A). The assay technology for IAbs has made great progress; however, several important aspects still need to be addressed and improved.

Recent findings: Currently a radio-binding assay has been well established as the 'gold' standard assay for all four IAbs. New generation of nonradioactive IAb assay with electrochemiluminescence technology has been shown to further improve sensitivity and disease specificity. Recently, multiplexed assays have opened the possibility of more efficient screening in large populations. Identification of potential new autoantibodies to neo-antigens or neo-epitopes posttranslational modification is a new important field to be explored.

Summary: Individuals having a single positive autoantibody are at low risk for progression to T1D, whereas individuals expressing two or more positive autoantibodies, especially on multiple tests over time, have nearly 100% risk of developing clinical T1D when followed for over two decades. More efficient and cost effective IAb assays will hopefully lead to point-of-care screening in the general population.

Figure 1

Comparison of predictive values between ECL and radioassays on 2,944 subjects for their very first initial screening samples in TrialNet Pathway to Prevention Study. Panel A: Comparison of positive predictive values between RBA-IAA (mIAA) and ECL-IAA (p<0.0001), and between RBA-GADA and ECL-GADA (p<0.0001). Panel B: Comparison of negative predictive values between RBA-IAA (mIAA) and ECL-IAA (p<0.05), and between RBA-GADA and ECL-GADA (p=0.007). [11] Diabetes Technol Ther. 2015;17:119–27.

Figure 2

Cumulative incidence of T1D development in subjects with single IAb in TrialNet Pathway to Prevention Study. Panel A: Cumulative incidence of T1D development in subjects with single GADA positive by RBA, divided with ECL-GADA positive vs ECL-GADA negative (p= 0.0009). Panel B: Cumulative incidence of T1D development in subjects with single IAA positive by RBA, divided with ECL-IAA positive vs ECL-IAA negative (p< 0.0001).

Figure 3

Development of diabetes by ECL status. A: All subjects (n = 1,287). B: Subjects positive for one autoantibody by RIAs (n = 902). C: Subjects positive for two or more autoantibodies by RBAs (n = 385). Survival analysis was performed for the development of diabetes since initial visit according to ECL positivity using the log-rank test. ECL-GADA/ECL-IAA pos, positive for both ECL-GADA and ECL-IAA; ECL-GADA pos, positive for ECL-GADA only; ECL-IAA pos, positive for ECL-IAA only; ECL-GADA/ECL-IAA neg, negative for both ECL-GADA and ECL-IAA. [13] Diabetes Care. 2016;39:1738–44.