Multiple antigens versus single major antigen in type 1 diabetes: arguing for multiple antigens

Our recent review of the literature revealed that approximately 20 antigens are now known to be targeted by T cells in the NOD mouse model of the autoimmune disease type 1 diabetes. Of these, insulin has received considerable attention and has been described by some in the research community as an 'initiating' or 'single major' antigen in the disease. Insulin may indeed be worthy of these titles, at least in NOD mice and in the context of the particular major histocompatibility complex molecules expressed in this strain. However, here we present arguments in favour of viewing type 1 diabetes as a disease in which multiple antigens should be considered, rather than just one. In our view, other antigens may prove to be more worthy of these titles in humans, and the major histocompatibility complex molecules expressed may well be a determining factor. Furthermore, even if insulin is 'the initiating antigen' in type 1 diabetes, multiple pathogenic specificities are known to exist even during the prediabetic period and it is at our peril that we ignore them. The recent discovery of novel beta-cell antigens, e.g. ZnT8 and chromogranin A, has taught us that we still have much to learn about the targets of the autoimmune response in type 1 diabetes. Increased knowledge will promote a clearer picture of disease pathogenesis and will better position the field to be successful in its translational goals of immune monitoring and disease prevention and reversal.