HIPs and HIP-reactive T cells

Abstract

Mounting evidence implicates hybrid insulin peptides (HIPs) as important autoantigens in the development of type 1 diabetes (T1D). These fusion peptides formed between insulin and other pancreatic beta cell-derived peptides contain non-genomically encoded amino acid sequences, making them plausible targets for autoreactive T cells in T1D. HIPs are detectable by mass spectrometry in human and murine islets and are targeted by diabetes-inducing T cells in non-obese diabetic mice as well as by T cells isolated from the residual pancreatic islets of human organ donors with T1D. The discovery of HIPs comes with numerous new challenges, as well as opportunities to study the pathogenesis of T1D. Here we review the original discovery of HIPs and describe recent studies investigating the role of HIP-reactive T cells in the development of diabetes. We also discuss potential mechanisms that may be responsible for the generation of HIPs in beta cells and describe challenges that need to be addressed in the field of mass spectrometry to enable the discovery of new HIPs. The identification of these potentially disease-driving antigens in T1D is of key interest to the field as it may provide new tools to predict, prevent and potentially reverse the disease.

Keywords: antigens; autoimmunity; diabetes; epitopes; peptides.

Figure 1

Hybrid peptide definition. Hybrid peptides form if peptides derived from two separate parent proteins are linked through a peptide bond. The resulting peptide contains a non‐genomically encoded amino acid sequence.

Figure 2

Potential mechanisms of hybrid peptide formation. A prerequisite for the formation of a hybrid peptide is the chemical activation of a peptide's C‐terminal carboxylic acid group prior to the formation of a new peptide bond. Such activation can occur through the formation of an intermediate between a peptide's C‐terminal carboxylic acid group and (a) a protease (thioester and ester) or (b) a phosphate‐group (mixed phosphoanhydrite).