The molecular specificity of insulin autoantibodies

Abstract

Insulin autoantibodies (IAA) are one of several markers for Type I (autoimmune) diabetes, but alone deserve special attention. Unlike the other markers, their ligand is unique to the beta cell. IAA are the first markers to appear during the symptomless period which precedes diabetes and they are present in the vast majority of young children destined to develop diabetes. The primary and tertiary structures of insulin have been known for decades. Binding studies with insulin variants have shown epitope restriction that can distinguish Type 1 diabetes-predictive from non-predictive IAA-positive sera, thereby improving specificity for the test. With two major international Type 1 diabetes prevention trials underway, there is a pressing need to refine markers that reliably indicate the presence of, and remission from, autoimmune insulitis. The binding regions of antibodies are assembled from three multi-gene families, and some of their diversity derives from random mutation during their antigen-driven maturation. There is evidence that mature IAA derive from germline-encoded 'natural' antibodies, and that the gene segments utilised by IAA may be influenced by clinical context. Monoclonal anti-idiotypic (anti-Id) antibodies can serve as probes for antibody variable region determinants, and antibodies to the different epitopes of beef and porcine insulins have already been analysed with monoclonal reagents. Used as antibodies in a radioimmunoassay format, monoclonal anti-Ids will identify and measure autoantibody idiotopes as if they were ligands. The challenge now is to replace the conventional radiobinding assays for IAA, which only detect and titrate, with radioimmunoassays that can be standardised in absolute units. There is sufficient evidence for the existence of Type 1 diabetes-predictive IAA idiotopes to justify the development of idiotope-specific radioimmunoassays which ignore Type 1 diabetes-unrelated IAA.