Date(s) - 03/10/2016
Immunopathology and Cell Biology of the GAD65 Autoantigen in Pancreatic Islets
Pancreatic islets of Langerhans are highly complex micro-societies of endocrine cells that control glucose homeostasis. They include insulin secreting beta cells, glucagon secreting alpha cells and somatostatin secreting delta cells. Autoimmune destruction of beta cells and beta cell dysfunction are central to the pathogenesis of type 1 and type 2 diabetes, respectively, which together incur health care costs in the hundreds of billions of dollars annually. Islet cells bear many striking similarities to neurons, including the production and secretion of neurotransmitter molecules. Glutamic acid decarboxylase 65 (GAD65), an enzyme, which catalyzes the decarboxylation of glutamate to produce the neurotransmitter GABA, is expressed in human pancreatic beta cells and is a major target autoantigen in human autoimmune diabetes. GABA is an important autocrine and paracrine signaling molecule and survival factor in islets. In this presentation I will describe our progress in understanding the cell biology and immunopathology of GAD65 in pancreatic islets during endoplasmic reticulum (ER) stress. Islet beta cells are particularly susceptible to ER stress, which is implicated in beta cell dysfunction and loss during the pathogenesis of both type 1 and type 2 diabetes. ER stress in primary rat and human beta cells perturbs the palmitoylation cycle that controls GAD65 endomembrane distribution, resulting in aberrant GAD65 accumulation in trans-Golgi membranes. Accumulation of GAD65 is restricted to the palmitoylated form, which exhibits increased uptake by antigen presenting cells and T cell stimulation. Similar accumulation of GAD65 in Golgi membranes is observed in beta cells in GAD65 autoantibody positive and T1D patients. We propose that aberrant accumulation of an immunogenic form of GAD65 in the trans-Golgi network may facilitate inappropriate presentation to the immune system following release from stressed beta cells. I will also present novel findings on the mechanisms of GABA synthesis and secretion in islet beta cells. Finally, I will report development of a novel method for culturing monolayers of primary islet cells on glass surfaces for live-cell and super-resolution microscopy that enables unprecedented visualization of subcellular processes in primary human and rat islet cells.
Dr. Edward Phelps is currently a postdoctoral fellow in the School of Life Science and the Institute of Bioengineering at the Swiss Federal Institute of Technology in Lausanne (EPFL), Switzerland. He received his B.S. in Biomedical Engineering from the Georgia Institute of Technology in 2006, and Ph.D. in Bioengineering from the Georgia Institute of Technology in 2011. Phelps’s thesis work focused on engineered bioactive materials for therapeutic angiogenesis and pancreatic islet transplantation for which he received the 2011 Georgia Tech Bioengineering Program Best Ph.D. Thesis Award. His current research focuses on pancreatic islet biology and immunoengineering. Phelps’s research has been supported by the American Heart Association, the Whitaker International Fellows and Scholars Program and most recently by a Juvenile Diabetes Research Foundation Advanced Postdoctoral Fellowship.