Immunomodulatory responses in the pancreas in health and disease

Abstract

Loss of β-cell mass is a key mechanism leading to the development of Type 1 diabetes (T1D). However, this process can be gradual with many patients retaining significant portions of their normal β-cell mass during the first 1-3 years from clinical diagnosis. The mechanisms underlying this progressive loss of β-cell mass are not fully elucidated but the ‘crosstalk’ between the immune system and β-cell has increasingly gained focus. The findings in this thesis challenge the notion that the islets of Langerhans are defenceless against an immune attack, and demonstrate that expression of immune checkpoint proteins PD-L1 and HLA-E are both present in individuals with T1D, and absent from donors without T1D. The expression of these proteins is associated with upregulation of interferon-stimulated genes, which are known to be active in early T1D pathogenesis. In addition, this thesis demonstrates that PD-L1 can be expressed on the surface of extracellular vesicles released from β-cell-like cells (EndoC-βH1 cells), potentially indicating a mechanism for β-cells to enhance binding of PD-L1 to PD-1 on cytotoxic T cells to negatively regulate the immune attack. The positive correlation between PD-L1 and levels of insulitis in T1D individuals indicates that PD-L1 on extracellular vesicles, in the future, may be able to act as biomarkers of disease progression. This thesis also explores the immunomodulatory responses in the pancreas when challenged by Type 3cDM diabetes associated with pancreatic ductal adenocarcinoma (PDAC). Findings indicate that individuals with diabetes and PDAC do not differ in immunologic profile compared to individuals with no diabetes, and therefore diabetes is not a marker for altering clinical management of PDAC. Finally, this thesis explored the epigenetic characterisation of a persistent coxsackie viral infection in pancreatic cells to demonstrate that no immunomodulatory mechanisms are altered with the establishment of persistence, but cells undergo changes in pathways for virus-host interactions, mitochondrial organisation, cellular protein catabolism, DNA damage responses and cellular responses to cadmium ions.