My research interests focus on understanding the pathology of human type 1 diabetes. I work in close collaboration with The Network for Pancreatic Donors with Diabetes (nPOD), a biorepository that provides valuable tissues from healthy and diabetic donors in order to answer questions about the pathogenesis of type 1 diabetes. Thanks to nPOD I found that CD8 T cells, the main cell type implicated in the destruction of insulin-producing beta cells, can be found in the islets of Langerhans predominantly when beta cells are still present but additionally infiltrate the exocrine pancreas in high numbers even when beta cells have been completely destroyed. I am working on identifying if these cells recognize beta cells antigens and their exact localization in the pancreas, spleen and lymph nodes in order to better understand the pathogenesis of the disease. I am also trying to elucidate whether viral infections make the islets more accessible for these destructive T cells or vice versa. Lastly, I am interested in studying if there is a defect in proinsulin processing and if post-translational modifications might occur during this process, leading to the formation of neo-epitopes that could be recognized by T cells. I am strongly committed to advance our understanding of the pathogenesis of type 1 diabetes in order to move the field forward.
A journey through the beta cell and beyond: proinsulin processing and immune recognition in type 1 diabetes.
Type 1 diabetes is a complex disease influenced by genetic and environmental factors in which the cells that produce insulin, called beta cells, and the immune system play a key role. Recent evidence suggests that beta cells might be contributing to their own destruction. One hypothesis is that when these highly specialized cells are stressed, they tend to produce errors and synthetize proteins that are not functional and accumulate in the cell. This might attract immune cells and trigger an autoimmune response in an attempt to eliminate these erroneous proteins. One of the proteins that might be affected is proinsulin, which is the precursor of insulin. Its synthesis accounts for 30-50% of the protein production in beta cells and it increases in response to insulin demand. Because of this high metabolic stress, beta cells might fail to correctly produce proinsulin, which could lead to the disruption of insulin production. The molecular mechanisms behind this phenomenon are not well understood and relatively few data are available from studies performed on humans. Our overall objective is to investigate insulin synthesis to provide a more complete understanding of the beta cell-immune interactions that occur during the development of type 1 diabetes.
In order to achieve this, we will obtain human samples from the Network for Pancreatic Organ Donors with diabetes (nPOD). We will study the human pancreas and we will determine the expression, cellular localization and processing of proinsulin in beta cells using state-of-art microscopy techniques. Then, we will use advance image analysis that combines machine-learning algorithms with automated software analysis. Finally, we will use super resolution microscopy to visualize potential proinsulin aggregations as well as specific interactions with its processing enzymes.
In the second part of the project, we will focus on investigating how the immune system recognizes proinsulin and insulin aggregations in individuals with type 1 diabetes. We will aim to detect antigen-specific CD8 T cells in different organs like duodenum, spleen, pancreas and lymph nodes and then use blood samples to investigate if the detection of these cells could be used as biomarkers or diagnostic tool.
By combining strategies that will study proinsulin and insulin from the perspective of the beta cell and the immune system, we will provide a complete overview of how insulin and its precursors are expressed and processed, the immune responses against them and how they change during disease development. Our approach includes new imaging technologies and analytical tools never used before in our field that will enable us to see inside the beta cell like never before. Ultimately, our work should help to develop novel biomarkers and therapeutic approaches targeting beta cell dysfunction possibly in combination with antigen specific therapies.