Shedding new light on the role of ERAP1 in Type 1 diabetes: A perspective on disease management.

Type 1 diabetes mellitus (T1D) is a multifactorial organ specific autoimmune disease which originates from the destruction of insulin-producing beta cells within the pancreatic islets by autoreactive CD8+ T lymphocytes. The autoimmune responses are raised against autoantigenic peptides presented in the context of the Major Histocompatibility Complex (MHC) class I molecules. Peptides are generated in the cytoplasm of the beta cell by degradation through the proteasome activity and other proteases. Proteolytic intermediate protein fragments are then vehicled into the endoplasmic reticulum (ER) by transporters associated with antigen processing TAP1 and TAP2. In the ER, Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the intermediate proteins to produce the optimal peptide size for loading into the MHC class I molecules. Subsequently complexes are shuttled to the cell surface for antigen presentation. Genome Wide Association Studies (GWAS) have identified different SNPs of ERAP1 associated to several autoimmune diseases and in particular the T1D-related ERAP1 SNP rs30187 encoding for K528R ERAP1. An association between the ER stress and the increased exposure of beta cells to the immune system has been hypothesized to further contribute to the etiopathogenesis. In particular in a recent study by Thomaidou et al. 2020 (doi: https://doi.org/10.2337/db19-0984) the posttranscriptional regulation of ERAP1 is shown to shaping the recognition of the preproinsulin (PPI) signal peptide by cytotoxic T lymphocytes. In the light of foregoing ERAP1 inhibitors could potentially prevent the activation of epitope-specific autoimmune-promoting T cells and their cytokine production; further regulating ERAP1 expression at posttranscriptional level under stress conditions of the beta cells could help to reverse autoimmune process through limiting epitope-presentation to autoreactive T cells. In this article we provide a perspective on the role of ERAP1 as implicated in the pathogenesis of insulin-dependent diabetes mellitus by reviewing studies reported in literature and discussing our own experimental evidence.