The insulin secretory granule is a hotspot for autoantigen formation in type 1 diabetes – published online 29/05/2024

Jason Groegler, Aïsha Callebaut, Eddie A. James, Thomas Delong

Insulin secretory granules play a crucial role in the formation of neoepitopes targeted by autoreactive T cells in type 1 diabetes. In this review, Groegler et al (https://doi.org/10.1007/s00125-024-06164-x) highlight the unique biochemical environment within these granules, characterised by an acidic pH, high protein concentration and the presence of various enzymes, which facilitates the generation of modified epitopes that may evade thymic selection processes. The authors discuss the interactions between preproinsulin epitopes and HLA, the role of preproinsulin expression and negative selection in the thymus, and the various mechanisms of neoepitope formation within insulin granules. These neoepitopes, including hybrid insulin peptides, deamidated epitopes and citrullinated epitopes, are discussed in detail. The authors also explore the therapeutic potential of targeting mechanisms of antigen formation within insulin granules to prevent the loss of tolerance and inhibit autoimmune destruction of insulin-producing beta cells. The authors conclude that a better understanding of these processes may provide valuable insights into disease pathogenesis and reveal new opportunities for therapeutic interventions. The figures from this review are available as a downloadable slideset.