Type 1 diabetes mellitus (T1D) is a multifactorial organ specific autoimmune disease which originates from thedestruction 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 MajorHistocompatibility Complex (MHC) class I molecules. Peptides are generated in the cytoplasm of the beta cell bydegradation through the proteasome activity and other proteases. Proteolytic intermediate protein fragments arethen vehicled into the endoplasmic reticulum (ER) by transporters associated with antigen processing TAP1 andTAP2.In the ER, Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the intermediate proteinsto produce the optimal peptide size for loading into the MHC class I molecules. Subsequently complexes areshuttled to the cell surface for antigen presentation.Genome Wide Association Studies (GWAS) have identified different SNPs of ERAP1 associated to severalautoimmune 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 beenhypothesized 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 shapingthe 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 throughlimiting epitope-presentation to autoreactive T cells.In this article we provide a perspective on the role of ERAP1 as implicated in the pathogenesis of insulindependent diabetes mellitus by reviewing studies reported in literature and discussing our own experimentalevidence.
Shedding new light on the role of ERAP1 in Type 1 diabetes: a perspective on disease management
Fierabracci A
2023-01-01
Abstract
Type 1 diabetes mellitus (T1D) is a multifactorial organ specific autoimmune disease which originates from thedestruction 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 MajorHistocompatibility Complex (MHC) class I molecules. Peptides are generated in the cytoplasm of the beta cell bydegradation through the proteasome activity and other proteases. Proteolytic intermediate protein fragments arethen vehicled into the endoplasmic reticulum (ER) by transporters associated with antigen processing TAP1 andTAP2.In the ER, Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the intermediate proteinsto produce the optimal peptide size for loading into the MHC class I molecules. Subsequently complexes areshuttled to the cell surface for antigen presentation.Genome Wide Association Studies (GWAS) have identified different SNPs of ERAP1 associated to severalautoimmune 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 beenhypothesized 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 shapingthe 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 throughlimiting epitope-presentation to autoreactive T cells.In this article we provide a perspective on the role of ERAP1 as implicated in the pathogenesis of insulindependent diabetes mellitus by reviewing studies reported in literature and discussing our own experimentalevidence.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
