Type 1 diabetes (T1D) is an autoimmune disease in which the insulin–producing β cells in the pancreas are selectively destroyed. Both genetic and environmental factors, such as viral infections, are implicated in the disease pathogenesis but how these factors contribute to the selective destruction of β cells at the cellular level remains unclear.
Accumulating data indicate that innate antiviral immune pathways (InAIPs), lysosomal cathepsin proteases, and T1D susceptibility genes play central roles in the development and progression of T1D. Genetic association studies have identified more than 140 genetic variants that influence T1D risk, including several risk variants localized to InAIP and cathepsin genes. Previous and preliminary studies of laser–dissected pancreatic islets have revealed differentially expressed InAIP and cathepsin genes in individuals with T1D compared to healthy individuals. However, the specific islet cells driving these changes and how they relate to disease stage or viral presence remain unknown, mainly due to the lack of spatially resolved data in human pancreatic tissue.
Using advanced spatial technologies, this project aims to pinpoint and investigate dysregulated genes, and their associated molecular and cellular pathways, involved in T1D pathogenesis, with emphasis on how InAIPs, cathepsins, and T1D susceptibility genes might act as biomarkers and/or mechanistic drivers of β–cell dysfunction and damage in T1D.
Spatial transcriptomics (Xenium) and spatial proteomics (MACSima) will be performed on neighbouring pancreatic tissue sections from healthy donors, autoantibody–positive (ab+) donors, and donors with new–onset T1D (≤ 6 months after disease onset). These analyses will reveal how disease–relevant genes and proteins are expressed in the different cell types within the pancreatic islets and surrounding tissue during the early disease stages, and how their spatial distribution relates to immune cell infiltration, viral infection and β–cell destruction. This will provide knowledge about their potential mechanistic roles in T1D, with the ultimate goal of identifying novel biomarkers of early T1D and therapeutic targets for future disease prevention and intervention strategies.
