How immune tolerance to pancreatic islets is lost in type 1 diabetes (T1D) is a central question in the field. Clues come from the cancer field, where CD4 and CD8 T-cell responses are detected to posttranslationally spliced proteins that form hybrid neoepitopes (1,2). The discovery of hybrid insulin peptides (HIPs) in pancreatic islets offers a potential mechanism for loss of tolerance to the target tissue in T1D. HIPs are formed by proteolytic processing in β-cell granules, resulting in peptides composed of noncontiguous amino acid sequences from the same protein or sequences from different β-cell proteins (3–5). As a result, T cells recognizing HIPs may not undergo deletion in the thymus due to a lack of expression of these nongenomically encoded peptides. In the context of an appropriate environmental trigger, high-risk HLA, and permissive immunoregulatory environment, HIP-reactive T cells may be activated and contribute to disease development.
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