Type I Diabetes: Encouraging the enemy
During their early life, immune cells learn to get along with the body’s own cells. In individuals with type 1 diabetes (T1D) that tolerance breaks down and immune cells selectively destroy insulin-producing beta cells in the pancreas. But pancreatic island cells may be complicit in their own demise.
Islet cells overexpress a surface protein known as MHC class I, whose job it is to present bits and pieces from cellular proteins to the immune system for closer inspection. MHC class I hyper-expression in the islets of recent-onset T1D patients was first reported about 30 years ago and continues to be a hot topic in the field as demonstrated by recent publications. But neither is there any evidence regarding the triggers or specific mechanisms that induce the elevated expression of MHC class I in the pancreatic islets, nor has its subcellular localization been thoroughly characterized.
Dr. Sabouri plans to obtain formalin-fixed paraffin-embedded tissue samples from human pancreata (non-diabetic, AAb+, and T1D donors) through the Network for Pancreatic Organ Donors with Diabetes (nPOD) to perform a standard triplet indirect immunofluorescence staining for insulin, glucagon and MHC class I. Her aim is to precisely define the intracellular localization of MHC class I through high-resolution laser scanning confocal microscopy (LSCM) and clearly define its association with islet cells. She is also interested in investigating the factors that trigger MHC class I expression such as interferon alpha or intracellular stress markers in the islets of T1D subjects and proposes to address the surface distribution of MHC class I and its localization with various endosomal markers such as early endosome antigen 1 (EEA1) or lysosomal-associated membrane protein 1-3 (LAMP1-3) and Golgi (GM130).
Dr. Sabouri’s current project will allow her to identify the surface distribution of MHC class I in the pancreas and the factors mediating MHC class I hyper – expression in the islets of donors with T1D. This study will provide novel information on a pathological abnormality that may reflect additional disease mechanisms, and how hyper-expression of MHC class I molecules may evolve during the progression of islet autoimmunity.