The beta cell immunopeptidome

Type 1 diabetes results from the autoimmune-mediated destruction of insulin-secreting beta cells, leading to beta cell loss and insulin deficiency. Presentation of peptides derived from beta cell proteins to autoreactive lymphocytes is critical for the development of disease, and the list of antigens recognized is increasing. A number of these proteins are found within the beta cell secretory granules, which are transiently exposed to the immune system during normal cellular function. How the interplay of environmental and genetic determinants culminates in destructive autoimmunity remains to be clearly defined. Nonconventional presentation of peptide ligands, posttranslational modification of peptides, and the role of the gut microbiome in the development of the immune system are all considered central topics in disease pathogenesis. Each of these may provide a mechanism by which presentation of antigenic peptides in the target tissue differs from presentation in the thymus, allowing autoreactive cells to escape tolerance induction. The high metabolic demand on pancreatic islets, the high concentration of granule proteins, and the susceptibility of islets to cellular stress may all contribute to the presentation of abnormal ligands in the pancreas. Moreover, the finding that small molecules can alter the repertoire of peptides presented by major histocompatibility complex molecules provides a tantalizing hypothesis for the presentation of autoantigenic peptides in the presence of microbial or endogenous metabolites. In this chapter, we provide an overview of the immunopeptidome of beta cells and the key factors that may influence presentation of beta cell antigens to the immune system.