The molecular specificity of insulin autoantibodies

Insulin autoantibodies (IAA) are one of several markers for Type I (autoimm une) diabetes, but alone deserve special attention. Unlike the other marker s, their ligand is unique to the beta cell. IAA are the first markers to ap pear during the symptomless period which precedes diabetes and they are pre sent in the vast majority of young children destined to develop diabetes. T he primary and tertiary structures of insulin have been known for decades. Binding studies with insulin variants have shown epitope restriction that c an distinguish Type 1 diabetes-predictive from non-predictive IAA-positive sera, thereby improving specificity for the test. With two major internatio nal 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 ma ture IAA derive from germline-encoded 'natural' antibodies, and that the ge ne segments utilised by IAA may be influenced by clinical context. Monoclon al anti-idiotypic (anti-Id) antibodies can serve as probes for antibody var iable 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 i dentify and measure autoantibody idiotopes as if they were ligands. The cha llenge now is to replace the conventional radiobinding assays for IAA, whic h 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-s pecific radioimmunoassays which ignore Type 1 diabetes-unrelated IAA. Copyr ight (C) 2000 John Wiley & Sons, Ltd.